U.S. patent application number 16/103830 was filed with the patent office on 2019-02-14 for rieske-type oxygenase/reductase targeted drugs for diagnostic and treatment of diseases.
The applicant listed for this patent is uBiome, Inc.. Invention is credited to Melissa Alegria, Daniel Almonacid, Zachary Apte, Ingrid Araya, Janyra Espinoza, Javier Gimpel, Luis Gomez, Valeria Marquez, Eduardo Morales, Rodrigo Ortiz, Jessica Richman, Mario Saavedra.
Application Number | 20190050525 16/103830 |
Document ID | / |
Family ID | 63449712 |
Filed Date | 2019-02-14 |
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United States Patent
Application |
20190050525 |
Kind Code |
A1 |
Apte; Zachary ; et
al. |
February 14, 2019 |
RIESKE-TYPE OXYGENASE/REDUCTASE TARGETED DRUGS FOR DIAGNOSTIC AND
TREATMENT OF DISEASES
Abstract
Embodiments of a method and/or system can include administering,
to a patient with one or more conditions associated with at least
one of TMA, TMAO, and/or derivatives thereof, a therapeutically
effective amount of a compound for affecting inhibiting one or more
CutC enzymes and/or CntA enzymes associated with microorganisms
from at least one taxon from a set of microorganism taxa.
Inventors: |
Apte; Zachary; (San
Francisco, CA) ; Richman; Jessica; (San Francisco,
CA) ; Almonacid; Daniel; (San Francisco, CA) ;
Marquez; Valeria; (Santiago, CL) ; Araya; Ingrid;
(Santiago, CL) ; Alegria; Melissa; (Santiago,
CL) ; Saavedra; Mario; (Santiago, CL) ; Gomez;
Luis; (Santiago, CL) ; Espinoza; Janyra;
(Santiago, CL) ; Gimpel; Javier; (Santiago,
CL) ; Morales; Eduardo; (Santiago, CL) ;
Ortiz; Rodrigo; (Santiago, CL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
uBiome, Inc. |
San Francisco |
CA |
US |
|
|
Family ID: |
63449712 |
Appl. No.: |
16/103830 |
Filed: |
August 14, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62545065 |
Aug 14, 2017 |
|
|
|
62545056 |
Aug 14, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 31/047 20130101; A61K 31/4406 20130101; A61K 31/4409 20130101;
A61K 31/166 20130101; A61K 31/216 20130101; A61P 13/12 20180101;
A61K 31/05 20130101; A61P 9/10 20180101; A61K 31/4196 20130101;
A61K 31/12 20130101; A61K 31/14 20130101; G16B 15/00 20190201; A61K
31/40 20130101; G16B 5/00 20190201; A61K 31/415 20130101; A61K
31/045 20130101 |
International
Class: |
G06F 19/16 20060101
G06F019/16; G06F 19/12 20060101 G06F019/12 |
Claims
1. A method for treating a patient with a condition associated with
at least one of trimethylamine (TMA), trimethylamine N-oxide
(TMAO), and derivatives thereof, the method comprising:
administering, to the patient with the condition, a therapeutically
effective amount of a compound for inhibiting choline
trimethylamine-lyase (CutC) enzymes of microorganisms from at least
one of Firmicutes (phylum) and Proteobacteria (phylum), wherein the
compound comprises at least one of: 2-Ethyl-1-butanol;
(2R)-3,3-Dimethyl-1,2-butanediol; (2S)-3,3-Dimethyl-1,2-butanediol;
(2S)-4-Methyl-2-pentanol; (2S)-3-Methyl-2-butanol;
(2R)-4-Methyl-2-pentanol; (2R)-3-Methyl-2-butanol; (2S)-2-Pentanol;
(2S)-2-Methyl-1,4-butanediol; 2-Methyl-2,4-butanediol;
Trimethylolpropane; 3-(4-Methoxyphenyl)propanal;
1-(3-Pyridinyl)-2-propanamine; 2-[(2R)-2-Butanyl]phenol;
4-Propylbenzoic acid; (2S)-1-(Benzyloxy)-2-propanol; Methyl
3-(4-hydroxyphenyl)propanoate; .alpha.-Methylphenylalanine;
2,2-Dimethyl-1-phenyl-1-propanol; Methyl
(2R)-hydroxy(phenyl)acetate; (2S)-2-Phenylpyrrolidinium;
4-Methyl-3-phenyl-1,2-oxazol-5-amine; 4,4'-Biphenyldiamine;
4'-Methyl-2-biphenylcarbonitrile; 4-Biphenylol;
2-[3-(4-Methylphenyl)-1,2-oxazol-5-yl]ethanol;
4-Biphenylcarboxamide; 4-Ethynylbiphenyl;
5-(4-Methylphenyl)-1H-1,2,4-triazol-3-amine;
5-(4-Methylphenyl)-1H-pyrazol-3-amine; 4-Hydroxycatechol;
3-Phenyl-1H-pyrazole-5-carbohydrazide; 4-Methyl-1,3-benzenediol;
N-(2-Hydroxyethyl)-1,3-propanediaminium; 3-Methoxy-3-methylbutanol;
4-Pyridinylmethanaminium; N-Methyl-3-pyridinamine;
2-Methoxypyridine; 5-Methyl-3-pyridinamine;
1-(4-Methyl-3-pyridinyl)methanamine; Mesitylene; (E)-Benzaldoxime`
(3R)-2,2,4-Trimethyl-1,3-pentanediol;
(1R,4R)-2-Azabicyclo[2.2.1]hept-2-ylacetic acid; 3-ACETYLPHENOL;
3-Hydroxybenzoicacid; 1H-Indol-7-ylmethanol; 3-Vinylaniline;
(3s,5s,7s)-1-Isocyanatoadamantane;
(1R,2S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one;
(-)-(3-Pinene; 2H-Isoindole-1,3-diamine; (3s,5s,7s)-1-Adamantanol;
(3-Aminobicyclo[2.2.1]hept-2-yl)methanol;
3-(Hydrazinomethyl)phenol; (1S,2R)-2-Carbamoylcyclohexanaminium;
(1S,4R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one;
(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one; Methyl
4-methyl-4-piperidinecarboxylate; Methyl heptanoate;
3-Methylpyridazine; 4,5-Dimethyl-1,2-oxazol-3-amine;
2-(2-Hydroxyethoxy)phenol;
2-Hydroxy-N-(3-pyridinylmethyl)ethanaminium; 3-Phenyl-1-propanol;
(2R)-6-Methyl-2-heptanol; 2-Phenoxyacetohydrazide;
N-Hydroxyoctanamid; Cyclobutanecarbohydrazide; Phenylhydrazine;
(1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one; salicylamide;
Adamantane; 3-Azabicyclo[3.3.1]nonane;
N-Hydroxy-2-methylbenzenecarboximidamide; (-)-camphene;
(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethanol; Dicyclopentadiene;
(8-anti)-3-Azabicyclo[3.2.1]octan-8-ol;
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6]deca-3,8-diene; pharmaceutically
acceptable forms thereof; and salts thereof.
2. The method of claim 1, wherein the condition comprises at least
one of a cardiovascular condition and a renal condition associated
with the at least one of TMA, TMAO, and derivatives thereof, and
wherein administering to the patient with the condition comprises
administering, to the patient with the at least one of the
cardiovascular condition and the renal condition, the
therapeutically effective amount of the compound for inhibiting the
CutC enzymes of the microorganisms from the at least one of
Firmicutes (phylum) and Proteobacteria (phylum).
3. The method of claim 2, wherein the condition comprises the
cardiovascular condition comprising an atherosclerosis condition
associated with the at least one of TMA, TMAO, and derivatives
thereof, and wherein administering to the patient with the
condition comprises administering, to the patient with the
atherosclerosis condition, the therapeutically effective amount of
the compound for inhibiting the CutC enzymes of the microorganisms
from the at least one of Firmicutes (phylum) and Proteobacteria
(phylum).
4. The method of claim 2, wherein the condition comprises the
cardiovascular condition comprising at least one of an enhanced
platelet aggregation condition and a thrombus formation condition
associated with the at least one of TMA, TMAO, and derivatives
thereof, and wherein administering to the patient with the
condition comprises administering, to the patient with the at least
one of the enhanced platelet aggregation condition and the thrombus
formation condition, the therapeutically effective amount of the
compound for inhibiting the CutC enzymes of the microorganisms from
the at least one of Firmicutes (phylum) and Proteobacteria
(phylum).
5. The method of claim 1, wherein administering to the patient with
the condition comprises administering, to the patient with the
condition, the therapeutically effective amount of the compound
comprising a 3,3-dimethyl-1-butanol (DMB) analogue comprising at
least one of: 2-Ethyl-1-butanol; (2R)-3,3-Dimethyl-1,2-butanediol;
(2S)-3,3-Dimethyl-1,2-butanediol; (2S)-4-Methyl-2-pentanol;
(2S)-3-Methyl-2-butanol; (2R)-4-Methyl-2-pentanol;
(2R)-3-Methyl-2-butanol; (2S)-2-Pentanol;
(2S)-2-Methyl-1,4-butanediol; 2-Methyl-2,4-butanediol;
Trimethylolpropane; pharmaceutically acceptable forms thereof; and
salts thereof.
6. The method of claim 1, wherein the microorganisms comprise
microorganisms from Firmicutes (phylum), wherein administering to
the patient with the condition comprises administering, to the
patient with the condition, the therapeutically effective amount of
the compound for inhibiting the CutC enzymes of the microorganisms
from Firmicutes (phylum), and wherein the compound comprises at
least one of: 3-(4-Methoxyphenyl)propanal;
1-(3-Pyridinyl)-2-propanamine; 2-[(2R)-2-Butanyl]phenol;
4-Propylbenzoic acid; (2S)-1-(Benzyloxy)-2-propanol; Methyl
3-(4-hydroxyphenyl)propanoate; .alpha.-Methylphenylalanine;
2,2-Dimethyl-1-phenyl-1-propanol; Methyl
(2R)-hydroxy(phenyl)acetate; (2S)-2-Phenylpyrrolidinium;
4-Methyl-3-phenyl-1,2-oxazol-5-amine; 4,4'-Biphenyldiamine;
4'-Methyl-2-biphenylcarbonitrile; 4-Biphenylol;
2-[3-(4-Methylphenyl)-1,2-oxazol-5-yl]ethanol;
4-Biphenylcarboxamide; 4-Ethynylbiphenyl;
5-(4-Methylphenyl)-1H-1,2,4-triazol-3-amine;
5-(4-Methylphenyl)-1H-pyrazol-3-amine; 4-Hydroxycatechol;
3-Phenyl-1H-pyrazole-5-carbohydrazide; 4-Methyl-1,3-benzenediol;
pharmaceutically acceptable forms thereof; and salts thereof.
7. The method of claim 1, wherein the microorganisms comprise
microorganisms from Proteobacteria (phylum), wherein administering
to the patient with the condition comprises administering, to the
patient with the condition, the therapeutically effective amount of
the compound for inhibiting the CutC enzymes of the microorganisms
from Proteobacteria (phylum), and wherein the compound comprises at
least one of: N-(2-Hydroxyethyl)-1,3-propanediaminium;
3-Methoxy-3-methylbutanol; 4-Pyridinylmethanaminium;
N-Methyl-3-pyridinamine; 2-Methoxypyridine;
5-Methyl-3-pyridinamine; 1-(4-Methyl-3-pyridinyl)methanamine;
Mesitylene; (E)-Benzaldoxime` (3R)-2,2,4-Trimethyl-1,3-pentanediol;
(1R,4R)-2-Azabicyclo[2.2.1]hept-2-ylacetic acid; 3-ACETYLPHENOL;
3-Hydroxybenzoicacid; 1H-Indol-7-ylmethanol; 3-Vinylaniline;
(3s,5s,7s)-1-Isocyanatoadamantane;
(1R,2S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one;
(-)-(3-Pinene; 2H-Isoindole-1,3-diamine; (3s,5s,7s)-1-Adamantanol;
(3-Aminobicyclo[2.2.1]hept-2-yl)methanol;
3-(Hydrazinomethyl)phenol; (1S,2R)-2-Carbamoylcyclohexanaminium;
(1S,4R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one;
(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one; pharmaceutically
acceptable forms thereof; and salts thereof.
8. The method of claim 1, wherein the microorganisms comprise
microorganisms from Firmicutes (phylum) and Proteobacteria
(phylum), wherein administering to the patient with the condition
comprises administering, to the patient with the condition, the
therapeutically effective amount of the compound for inhibiting the
CutC enzymes of the microorganisms from Firmicutes (phylum) and
Proteobacteria (phylum), and wherein the compound comprises at
least one of: Methyl 4-methyl-4-piperidinecarboxylate; Methyl
heptanoate; 3-Methylpyridazine; 4,5-Dimethyl-1,2-oxazol-3-amine;
2-(2-Hydroxyethoxy)phenol;
2-Hydroxy-N-(3-pyridinylmethyl)ethanaminium; 3-Phenyl-1-propanol;
(2R)-6-Methyl-2-heptanol; 2-Phenoxyacetohydrazide;
N-Hydroxyoctanamid; Cyclobutanecarbohydrazide; Phenylhydrazine;
(1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one; salicylamide;
Adamantane; 3-Azabicyclo[3.3.1]nonane;
N-Hydroxy-2-methylbenzenecarboximidamide; (-)-camphene;
(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethanol; Dicyclopentadiene;
(8-anti)-3-Azabicyclo[3.2.1]octan-8-ol;
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6]deca-3,8-diene; pharmaceutically
acceptable forms thereof; and salts thereof.
9. A method for treating a patient with a condition associated with
at least one of trimethylamine (TMA), trimethylamine N-oxide
(TMAO), and derivatives thereof, the method comprising:
administering, to the patient with the condition, a therapeutically
effective amount of a compound for inhibiting Rieske-type oxygenase
(CntA) enzymes of microorganisms from at least one of Firmicutes
(phylum) and Proteobacteria (phylum), wherein the compound
comprises at least one of: N-Methylglutamic acid;
4-(1-Pyrrolidinyl)butanoic acid; 4-Methyl-4-piperidinecarboxylic
acid; Isonipecotic acid; N-propylbenzene; N-Ethyl-2-pyridinamine;
(4R)-4-Amino-1-propyl-2-pyrrolidinone; 2,5-Diaminotoluene; Ethyl
phenyl ether; Phenylcyanate; 1-(2-Cyclopenten-1-yl)acetone;
2-Amino-3-methylpyridinium; E-pyridine-3-aldoxime;
N-Cyclohexylformamide; 2-Methyl-2-hexenoic acid; 4-Heptanaminium;
3,4-Anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid;
2,2'-[(2-Hydroxyethyl)imino]diacetic acid; 1H-Tetrazol-5-ylacetic
acid; Diacetylacetone; (2S)-2-Acetoxypropanoic acid;
4,4'-Biphthalic anhydride; Bis(1H-benzotriazol-1-yl)methanone;
2-Anthraquinonesulfonic acid;
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile;
2-phenylquinazolin-4-ol; 4-Amino-2-(1,3-benzothiazol-2-yl)phenol;
4-Phenyl-1(2H)-phthalazinone;
5-(1,3-Benzodioxol-5-yl)-2-methyl-3-furoic acid;
(5R)-5-(2-Naphthyl)dihydro-2(3H)-furanone;
3-[5-(3-Methylphenyl)-1,3,4-oxadiazol-2-yl]propanoic acid;
9-ETHYNYLPHENANTHRENE; PHA-767491; 3-Amino-2-methylphenol;
5-(4-Methylphenyl)-2-furoic acid;
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid; resorcinol
monobenzoate; 3-Methoxy-4-biphenylcarbaldehyde;
(7-Amino-4-methyl-2-oxo-2H-chromen-3-yl)acetic acid;
2,3-Dihydro-1H-inden-5-yl(oxo)acetic acid; 3-(2-Pyridyl)aniline;
4-(3-Methyl-1H-1,2,4-triazol-5-yl)aniline; Benzidine;
(DL)-3-O-Methyldopa; Methyl
(2E)-3-(2-amino-5-methyl-3-pyridinyl)acrylate;
(5-Methylfuro[2,3-b]pyridin-2-yl)methanol;
(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethanaminium; R-phenylethyl
propionate; i-propyl benzoate; 4-Acetotoluide;
(1S)-1-(2,5-Dimethylphenyl)ethanaminium;
(1R)-2-Methyl-2,5-cyclohexadiene-1-carboxylic acid;
(2,2-Dimethoxyethyl)benzene; pharmaceutically acceptable forms
thereof; and salts thereof.
10. The method of claim 9, wherein the condition comprises at least
one of a cardiovascular condition and a renal condition associated
with the at least one of TMA, TMAO, and derivatives thereof, and
wherein administering to the patient with the condition comprises
administering, to the patient with the at least one of the
cardiovascular condition and the renal condition, the
therapeutically effective amount of the compound for inhibiting the
CntA enzymes of the microorganisms from the at least one of
Firmicutes (phylum) and Proteobacteria (phylum).
11. The method of claim 10, wherein the condition comprises the
cardiovascular condition comprising an atherosclerosis condition
associated with the at least one of TMA, TMAO, and derivatives
thereof, and wherein administering to the patient with the
condition comprises administering, to the patient with the
atherosclerosis condition, the therapeutically effective amount of
the compound for inhibiting the CntA enzymes of the microorganisms
from the at least one of Firmicutes (phylum) and Proteobacteria
(phylum).
12. The method of claim 10, wherein the condition comprises the
cardiovascular condition comprising at least one of an enhanced
platelet aggregation condition and a thrombus formation condition
associated with the at least one of TMA, TMAO, and derivatives
thereof, and wherein administering to the patient with the
condition comprises administering, to the patient with the at least
one of the enhanced platelet aggregation condition and the thrombus
formation condition, the therapeutically effective amount of the
compound for inhibiting the CntA enzymes of the microorganisms from
the at least one of Firmicutes (phylum) and Proteobacteria
(phylum).
13. The method of claim 9, wherein the condition comprises at least
one of a metabolic-related condition and a nutrition-related
condition associated with the at least one of TMA, TMAO, and
derivatives thereof, and wherein administering to the patient with
the condition comprises administering, to the patient with the at
least one of the metabolic-related condition and the
nutrition-related condition, the therapeutically effective amount
of the compound for inhibiting the CntA enzymes of the
microorganisms from the at least one of Firmicutes (phylum) and
Proteobacteria (phylum).
14. The method of claim 13, wherein the at least one of the
metabolic-related condition and the nutrition-related condition
comprises at least one a weight-related condition and a high blood
sugar-related condition associated with the at least one of TMA,
TMAO, and derivatives thereof, and wherein administering to the
patient with the condition comprises administering, to the patient
with the at least one the weight-related condition and the high
blood sugar-related condition, the therapeutically effective amount
of the compound for inhibiting the CntA enzymes of the
microorganisms from the at least one of Firmicutes (phylum) and
Proteobacteria (phylum).
15. The method of claim 13, wherein the condition comprises the
metabolic-related condition comprising a trimethylaminuria (TMAU)
condition associated with the at least one of TMA, TMAO, and
derivatives thereof, and wherein administering to the patient with
the condition comprises administering, to the patient with the TMAU
condition, the therapeutically effective amount of the compound for
inhibiting the CntA enzymes of the microorganisms from the at least
one of Firmicutes (phylum) and Proteobacteria (phylum).
16. The method of claim 9, wherein administering to the patient
with the condition comprises administering, to the patient with the
condition, the therapeutically effective amount of the compound
comprising an L-carnitine analogue comprising at least one of:
N-Methylglutamic acid; 4-(1-Pyrrolidinyl)butanoic acid;
4-Methyl-4-piperidinecarboxylic acid; Isonipecotic acid;
pharmaceutically acceptable forms thereof; and salts thereof.
17. The method of claim 9, wherein the microorganisms comprise
microorganisms from Firmicutes (phylum), wherein administering to
the patient with the condition comprises administering, to the
patient with the condition, the therapeutically effective amount of
the compound for inhibiting the CntA enzymes of the microorganisms
from Firmicutes (phylum), and wherein the compound comprises at
least one of: N-propylbenzene; N-Ethyl-2-pyridinamine;
(4R)-4-Amino-1-propyl-2-pyrrolidinone; 2,5-Diaminotoluene; Ethyl
phenyl ether; Phenylcyanate; 1-(2-Cyclopenten-1-yl)acetone;
2-Amino-3-methylpyridinium; E-pyridine-3-aldoxime;
N-Cyclohexylformamide; 2-Methyl-2-hexenoic acid; 4-Heptanaminium;
pharmaceutically acceptable forms thereof; and salts thereof.
18. The method of claim 9, wherein the microorganisms comprise
microorganisms from Proteobacteria (phylum), wherein administering
to the patient with the condition comprises administering, to the
patient with the condition, the therapeutically effective amount of
the compound for inhibiting the CntA enzymes of the microorganisms
from Proteobacteria (phylum), and wherein the compound comprises at
least one of: 3,4-Anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid;
2,2'-[(2-Hydroxyethyl)imino]diacetic acid; 1H-Tetrazol-5-ylacetic
acid; Diacetylacetone; (2S)-2-Acetoxypropanoic acid;
pharmaceutically acceptable forms thereof; and salts thereof.
19. The method of claim 9, wherein the microorganisms comprise
microorganisms from Firmicutes (phylum) and Proteobacteria
(phylum), wherein administering to the patient with the condition
comprises administering, to the patient with the condition, the
therapeutically effective amount of the compound for inhibiting the
CntA enzymes of the microorganisms from Firmicutes (phylum) and
Proteobacteria (phylum), and wherein the compound comprises at
least one of: 4,4'-Biphthalic anhydride;
Bis(1H-benzotriazol-1-yl)methanone; 2-Anthraquinonesulfonic acid;
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile;
2-phenylquinazolin-4-ol; 4-Amino-2-(1,3-benzothiazol-2-yl)phenol;
4-Phenyl-1(2H)-phthalazinone;
5-(1,3-Benzodioxol-5-yl)-2-methyl-3-furoic acid;
(5R)-5-(2-Naphthyl)dihydro-2(3H)-furanone;
3-[5-(3-Methylphenyl)-1,3,4-oxadiazol-2-yl]propanoic acid;
9-ETHYNYLPHENANTHRENE; PHA-767491; 3-Amino-2-methylphenol;
5-(4-Methylphenyl)-2-furoic acid;
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid; resorcinol
monobenzoate; 3-Methoxy-4-biphenylcarbaldehyde;
(7-Amino-4-methyl-2-oxo-2H-chromen-3-yl)acetic acid;
2,3-Dihydro-1H-inden-5-yl(oxo)acetic acid; 3-(2-Pyridyl)aniline;
4-(3-Methyl-1H-1,2,4-triazol-5-yl)aniline; Benzidine;
(DL)-3-O-Methyldopa; Methyl
(2E)-3-(2-amino-5-methyl-3-pyridinyl)acrylate;
(5-Methylfuro[2,3-b]pyridin-2-yl)methanol;
(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethanaminium; R-phenylethyl
propionate; i-propyl benzoate; 4-Acetotoluide;
(1S)-1-(2,5-Dimethylphenyl)ethanaminium;
(1R)-2-Methyl-2,5-cyclohexadiene-1-carboxylic acid;
(2,2-Dimethoxyethyl)benzene; pharmaceutically acceptable forms
thereof; and salts thereof.
20. A method for identifying at least one compound for treating a
patient with a condition associated with at least one of
trimethylamine (TMA), trimethylamine N-oxide (TMAO), and
derivatives thereof, the method comprising: determining a
representative sequence of an enzyme associated with the at least
one of TMA, TMAO, and derivatives thereof, wherein the
representative sequence is representative of a set of sequences of
the enzyme for at least one taxon from a set of microorganism taxa;
generating a protein structure model of the enzyme based on the
representative sequence of the enzyme; determining a control
binding parameter to the enzyme based on a control docking
simulation with the protein structure model and a control molecule;
determining a set of compound binding parameters to the enzyme
based on a set of compound docking simulations with the protein
structure model and a library of compounds; and identifying the at
least one compound, from the library of compounds, for treating the
patient with the condition associated with the at least one of TMA,
TMAO, and derivatives thereof, based on a comparison between the
control binding parameter and the set of compound binding
parameters.
21. The method of claim 20, wherein the enzyme comprises at least
one of choline trimethylamine-lyase (CutC) enzyme and Rieske-type
oxygenase (CntA) enzyme, and wherein the at least one taxon
comprises at least one of Firmicutes (phylum) and Proteobacteria
(phylum).
22. The method of claim 21, wherein the at least one compound
comprises at least one of 2-Ethyl-1-butanol;
(2R)-3,3-Dimethyl-1,2-butanediol; (2S)-3,3-Dimethyl-1,2-butanediol;
(2S)-4-Methyl-2-pentanol; (2S)-3-Methyl-2-butanol;
(2R)-4-Methyl-2-pentanol; (2R)-3-Methyl-2-butanol; (2S)-2-Pentanol;
(2S)-2-Methyl-1,4-butanediol; 2-Methyl-2,4-butanediol;
Trimethylolpropane; 3-(4-Methoxyphenyl)propanal;
1-(3-Pyridinyl)-2-propanamine; 2-[(2R)-2-Butanyl]phenol;
4-Propylbenzoic acid; (2S)-1-(Benzyloxy)-2-propanol; Methyl
3-(4-hydroxyphenyl)propanoate; .alpha.-Methylphenylalanine;
2,2-Dimethyl-1-phenyl-1-propanol; Methyl
(2R)-hydroxy(phenyl)acetate; (2S)-2-Phenylpyrrolidinium;
4-Methyl-3-phenyl-1,2-oxazol-5-amine; 4,4'-Biphenyldiamine;
4'-Methyl-2-biphenylcarbonitrile; 4-Biphenylol;
2-[3-(4-Methylphenyl)-1,2-oxazol-5-yl]ethanol;
4-Biphenylcarboxamide; 4-Ethynylbiphenyl;
5-(4-Methylphenyl)-1H-1,2,4-triazol-3-amine;
5-(4-Methylphenyl)-1H-pyrazol-3-amine; 4-Hydroxycatechol;
3-Phenyl-1H-pyrazole-5-carbohydrazide; 4-Methyl-1,3-benzenediol;
N-(2-Hydroxyethyl)-1,3-propanediaminium; 3-Methoxy-3-methylbutanol;
4-Pyridinylmethanaminium; N-Methyl-3-pyridinamine;
2-Methoxypyridine; 5-Methyl-3-pyridinamine;
1-(4-Methyl-3-pyridinyl)methanamine; Mesitylene; (E)-Benzaldoxime`
(3R)-2,2,4-Trimethyl-1,3-pentanediol;
(1R,4R)-2-Azabicyclo[2.2.1]hept-2-ylacetic acid; 3-ACETYLPHENOL;
3-Hydroxybenzoicacid; 1H-Indol-7-ylmethanol; 3-Vinylaniline;
(3s,5s,7s)-1-Isocyanatoadamantane;
(1R,2S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one;
(-)-(3-Pinene; 2H-Isoindole-1,3-diamine; (3s,5s,7s)-1-Adamantanol;
(3-Aminobicyclo[2.2.1]hept-2-yl)methanol;
3-(Hydrazinomethyl)phenol; (1S,2R)-2-Carbamoylcyclohexanaminium;
(1S,4R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one;
(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one; Methyl
4-methyl-4-piperidinecarboxylate; Methyl heptanoate;
3-Methylpyridazine; 4,5-Dimethyl-1,2-oxazol-3-amine;
2-(2-Hydroxyethoxy)phenol;
2-Hydroxy-N-(3-pyridinylmethyl)ethanaminium; 3-Phenyl-1-propanol;
(2R)-6-Methyl-2-heptanol; 2-Phenoxyacetohydrazide;
N-Hydroxyoctanamid; Cyclobutanecarbohydrazide; Phenylhydrazine;
(1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one; salicylamide;
Adamantane; 3-Azabicyclo[3.3.1]nonane;
N-Hydroxy-2-methylbenzenecarboximidamide; (-)-camphene;
(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethanol; Dicyclopentadiene;
(8-anti)-3-Azabicyclo[3.2.1]octan-8-ol;
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6]deca-3,8-diene; N-Methylglutamic
acid; 4-(1-Pyrrolidinyl)butanoic acid;
4-Methyl-4-piperidinecarboxylic acid; Isonipecotic acid;
N-propylbenzene; N-Ethyl-2-pyridinamine;
(4R)-4-Amino-1-propyl-2-pyrrolidinone; 2,5-Diaminotoluene; Ethyl
phenyl ether; Phenylcyanate; 1-(2-Cyclopenten-1-yl)acetone;
2-Amino-3-methylpyridinium; E-pyridine-3-aldoxime;
N-Cyclohexylformamide; 2-Methyl-2-hexenoic acid; 4-Heptanaminium;
3,4-Anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid;
2,2'-[(2-Hydroxyethyl)imino]diacetic acid; 1H-Tetrazol-5-ylacetic
acid; Diacetylacetone; (2S)-2-Acetoxypropanoic acid;
4,4'-Biphthalic anhydride; Bis(1H-benzotriazol-1-yl)methanone;
2-Anthraquinonesulfonic acid;
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile;
2-phenylquinazolin-4-ol; 4-Amino-2-(1,3-benzothiazol-2-yl)phenol;
4-Phenyl-1(2H)-phthalazinone;
5-(1,3-Benzodioxol-5-yl)-2-methyl-3-furoic acid;
(5R)-5-(2-Naphthyl)dihydro-2(3H)-furanone;
3-[5-(3-Methylphenyl)-1,3,4-oxadiazol-2-yl]propanoic acid;
9-ETHYNYLPHENANTHRENE; PHA-767491; 3-Amino-2-methylphenol;
5-(4-Methylphenyl)-2-furoic acid;
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid; resorcinol
monobenzoate; 3-Methoxy-4-biphenylcarbaldehyde;
(7-Amino-4-methyl-2-oxo-2H-chromen-3-yl)acetic acid;
2,3-Dihydro-1H-inden-5-yl(oxo)acetic acid; 3-(2-Pyridyl)aniline;
4-(3-Methyl-1H-1,2,4-triazol-5-yl)aniline; Benzidine;
(DL)-3-O-Methyldopa; Methyl
(2E)-3-(2-amino-5-methyl-3-pyridinyl)acrylate;
(5-Methylfuro[2,3-b]pyridin-2-yl)methanol;
(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethanaminium; R-phenylethyl
propionate; i-propyl benzoate; 4-Acetotoluide;
(1S)-1-(2,5-Dimethylphenyl)ethanaminium;
(1R)-2-Methyl-2,5-cyclohexadiene-1-carboxylic acid;
(2,2-Dimethoxyethyl)benzene; pharmaceutically acceptable forms
thereof; and salts thereof.
23. The method of claim 22, wherein the condition comprises at
least one of a cardiovascular condition, a renal condition, a
metabolic-related condition, and a nutrition-related condition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 62/545,056 filed 14 Aug. 2017, which is herein
incorporated in its entirety by this reference. This application
additionally claims the benefit of U.S. Provisional Application
Ser. No. 62/545,065 filed 14 Aug. 2017, which is herein
incorporated in its entirety by this reference.
TECHNICAL FIELD
[0002] The disclosure generally relates to microbiology.
BACKGROUND
[0003] The concept of drugging microbial targets (e.g., drugging
the microbiome, etc.) can include one or more therapeutic
approaches avoiding targeting human cells directly, and/or avoiding
side effects derived from gene therapy; and instead targeting
receptors and enzymes belonging to microbiota. Such approaches can
avoid knocking-down the action of human enzymes by gene therapy
methods, where such enzymes are not only possibly involved in the
production of undesirable metabolites, but can also exert
beneficial effects on the organism.
[0004] Choline is a crucial nutrient for humans and other
organisms, contributing to different roles in biological pathways
as cell membrane function, methyl transfer events, and
neurotransmission. In addition to choline, the trimethylamine (TMA)
metabolite is an important source of nitrogen, and it is also a
carbon source for bacteria that convert TMA in greenhouse gas
methane in marine environments. These small molecules are connected
through the choline trimethylamine-lyase (CutC) enzyme, which is a
glycine radical enzyme that performs the cleavage of the C--N bond
in choline to produce trimethylamine (TMA) and acetaldehyde as
follows: Choline=trimethylamine+acetaldehyde.
[0005] Gut bacteria and/or other suitable microorganisms from any
suitable body sites can play a critical role in triggering and
progression of some diseases. Human gut microbiota has been
described as producing TMA from choline; a process that is
exclusively found in microbes. Choline degradation is the major
source of TMA formation within the intestines. Specifically, gut
bacteria diet can have an incidence on the production of TMA and
its derivative product trimethylamine-N-oxide (TMAO). For example,
TMA metabolite, which is often obtained from meat, egg (e.g., egg
yolk, etc.), fat-rich food, and/or dairy products is absorbed and
converted to TMAO in the liver by the action of the human
Flavin-containing monooxygenase 3 (FMO3) enzyme.
[0006] Patients having high TMA levels display higher probabilities
of suffering a heart attack. These aspects have become particularly
relevant when recent studies have discarded that saturated fats and
cholesterol are correlated with an increased risk of heart diseases
and atherosclerosis.
[0007] TMAO is a metabolite that has been associated with a high
risk of cardiovascular and renal diseases, and additionally, high
levels of TMAO produced from choline can trigger atherosclerosis in
mice. Two main TMA synthesis pathways have been described in
bacteria, one using choline as a substrate (CutC/CutD complex) and
the other one using L-carnitine (the two-component Rieske-type
oxygenase/reductase CntA/B). Genes encoding CntA/B have been
described in several taxa belonging to Betaproteobacteria as well
as from a few Firmicutes.
[0008] Regarding one of the main TMA synthesis pathways described,
the pathway uses choline as a substrate (CutC/CutD complex). TMA is
absorbed and is converted in the liver to TMAO by the action of the
FMO3 enzyme. FMO3 participates in host-gut microbiota metabolic
interactions. Some strategies have proposed to knock-down the
expression of FMO3 enzymes using antisense oligonucleotides that
inhibit transcription of its mRNA. While directly reducing choline
or L-carnitine ingestion may produce undesired effects, since these
molecules can be beneficial in lower quantities, inhibiting FMO3
enzyme to reduce TMAO levels can also undesirable, because
accumulation of TMA produces (e.g., through suppression of FMO3
enzymes) conditions or side effects such as hepatic inflammation
and/or trimethylaminuria (e.g., fish odor syndrome; fish malodor
disorder; etc.).
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1 includes a flowchart representation of variations of
an embodiment of a method;
[0010] FIG. 2 includes a flowchart representation of variations of
an embodiment of a method;
[0011] FIG. 3 includes a graphical representation of variations of
an embodiment of a method.
DESCRIPTION OF THE EMBODIMENTS
[0012] The following description of the embodiments is not intended
to limit the embodiments, but rather to enable any person skilled
in the art to make and use.
1. Overview
[0013] As shown in FIGS. 1-3, embodiments of a method 100 (e.g.,
for treating a patient with a condition associated with at least
one of TMA, TMAO, and/or derivatives thereof; etc.) can include
administering, to a patient with one or more conditions (e.g., one
or more conditions associated with the at least one of TMA, TMAO,
and/or derivatives thereof; etc.), a therapeutically effective
amount of a compound (e.g., drug; etc.) for affecting (e.g.,
inhibiting; etc.) one or more targets Silo (e.g., CutC enzymes;
Rieske-type oxygenase (CntA) enzymes; other enzymes; proteins;
other biological targets; non-biological targets; enzymes
associated with at least one of TMA, TMAO, and/or derivatives
thereof; etc.) associated with microorganisms from at least one
taxon from a set of microorganism taxa (e.g., from at least one of
Firmicutes (phylum) and Proteobacteria (phylum); etc.).
[0014] In an example, a method 100 (e.g., for treating a patient
with one or more conditions associated with at least one of TMA,
TMAO, and/or derivatives thereof; etc.) can include administering,
to the patient with the one or more conditions, a therapeutically
effective amount of a compound for inhibiting CutC enzymes of
microorganisms from at least one of Firmicutes (phylum) and
Proteobacteria (phylum), where the compound (e.g., including one or
more constituents, such as any suitable combination of
constituents; etc.) includes at least one of: 2-Ethyl-1-butanol;
(2R)-3,3-Dimethyl-1,2-butanediol; (2S)-3,3-Dimethyl-1,2-butanediol;
(2S)-4-Methyl-2-pentanol; (2S)-3-Methyl-2-butanol;
(2R)-4-Methyl-2-pentanol; (2R)-3-Methyl-2-butanol; (2S)-2-Pentanol;
(2S)-2-Methyl-1,4-butanediol; 2-Methyl-2,4-butanediol;
Trimethylolpropane; 3-(4-Methoxyphenyl)propanal;
1-(3-Pyridinyl)-2-propanamine; 2-[(2R)-2-Butanyl]phenol;
4-Propylbenzoic acid; (2S)-1-(Benzyloxy)-2-propanol; Methyl
3-(4-hydroxyphenyl)propanoate; .alpha.-Methylphenylalanine;
2,2-Dimethyl-1-phenyl-1-propanol; Methyl
(2R)-hydroxy(phenyl)acetate; (2S)-2-Phenylpyrrolidinium;
4-Methyl-3-phenyl-1,2-oxazol-5-amine; 4,4'-Biphenyldiamine;
4'-Methyl-2-biphenylcarbonitrile; 4-Biphenylol;
2-[3-(4-Methylphenyl)-1,2-oxazol-5-yl] ethanol;
4-Biphenylcarboxamide; 4-Ethynylbiphenyl;
5-(4-Methylphenyl)-1H-1,2,4-triazol-3-amine;
5-(4-Methylphenyl)-1H-pyrazol-3-amine; 4-Hydroxycatechol;
3-Phenyl-1H-pyrazole-5-carbohydrazide; 4-Methyl-1,3-benzenediol;
N-(2-Hydroxyethyl)-1,3-propanediaminium; 3-Methoxy-3-methylbutanol;
4-Pyridinylmethanaminium; N-Methyl-3-pyridinamine;
2-Methoxypyridine; 5-Methyl-3-pyridinamine;
1-(4-Methyl-3-pyridinyl)methanamine; Mesitylene; (E)-Benzaldoxime`
(3R)-2,2,4-Trimethyl-1,3-pentanediol;
(1R,4R)-2-Azabicyclo[2.2.1]hept-2-ylacetic acid; 3-ACETYLPHENOL;
3-Hydroxybenzoicacid; 1H-Indol-7-ylmethanol; 3-Vinylaniline;
(3s,5s,7s)-1-Isocyanatoadamantane;
(1R,2S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one;
(-)-.beta.-Pinene; 2H-Isoindole-1,3-diamine;
(3s,5s,7s)-1-Adamantanol; (3-Aminobicyclo[2.2.1]hept-2-yl)methanol;
3-(Hydrazinomethyl)phenol; (1S,2R)-2-Carbamoylcyclohexanaminium;
(1S,4R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one;
(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one; Methyl
4-methyl-4-piperidinecarboxylate; Methyl heptanoate;
3-Methylpyridazine; 4,5-Dimethyl-1,2-oxazol-3-amine;
2-(2-Hydroxyethoxy)phenol;
2-Hydroxy-N-(3-pyridinylmethyl)ethanaminium; 3-Phenyl-1-propanol;
(2R)-6-Methyl-2-heptanol; 2-Phenoxyacetohydrazide;
N-Hydroxyoctanamid; Cyclobutanecarbohydrazide; Phenylhydrazine;
(1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one; salicylamide;
Adamantane; 3-Azabicyclo[3.3.1]nonane;
N-Hydroxy-2-methylbenzenecarboximidamide; (-)-camphene;
(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethanol; Dicyclopentadiene;
(8-anti)-3-Azabicyclo[3.2.1]octan-8-ol;
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6]deca-3,8-diene; any suitable
compounds including any suitable combination of any suitable
compounds and/or structures (e.g., of one or more structures; etc.)
included in Tables 1-4; and/or any pharmaceutically acceptable
forms thereof; and/or salts of thereof.
[0015] In an example, a method 100 (e.g., for treating a patient
with one or more conditions associated with at least one of TMA,
TMAO, and/or derivatives thereof; etc.) can include administering,
to the patient with the one or more conditions, a therapeutically
effective amount of a compound for inhibiting CntA enzymes of
microorganisms from at least one of Firmicutes (phylum) and
Proteobacteria (phylum), where the compound (e.g., including one or
more constituents, such as any suitable combination of
constituents; etc.) includes at least one of: N-Methylglutamic
acid; 4-(1-Pyrrolidinyl)butanoic acid;
4-Methyl-4-piperidinecarboxylic acid; Isonipecotic acid;
N-propylbenzene; N-Ethyl-2-pyridinamine;
(4R)-4-Amino-1-propyl-2-pyrrolidinone; 2,5-Diaminotoluene; Ethyl
phenyl ether; Phenylcyanate; 1-(2-Cyclopenten-1-yl)acetone;
2-Amino-3-methylpyridinium; E-pyridine-3-aldoxime;
N-Cyclohexylformamide; 2-Methyl-2-hexenoic acid; 4-Heptanaminium;
3,4-Anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid;
2,2'-[(2-Hydroxyethyl)imino]diacetic acid; 1H-Tetrazol-5-ylacetic
acid; Diacetylacetone; (2S)-2-Acetoxypropanoic acid;
4,4'-Biphthalic anhydride; Bis(1H-benzotriazol-1-yl)methanone;
2-Anthraquinonesulfonic acid;
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile;
2-phenylquinazolin-4-ol; 4-Amino-2-(1,3-benzothiazol-2-yl)phenol;
4-Phenyl-1(2H)-phthalazinone;
5-(1,3-Benzodioxol-5-yl)-2-methyl-3-furoic acid;
(5R)-5-(2-Naphthyl)dihydro-2(3H)-furanone;
3-[5-(3-Methylphenyl)-1,3,4-oxadiazol-2-yl]propanoic acid;
9-ETHYNYLPHENANTHRENE; PHA-767491; 3-Amino-2-methylphenol;
5-(4-Methylphenyl)-2-furoic acid;
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid; resorcinol
monobenzoate; 3-Methoxy-4-biphenylcarbaldehyde;
(7-Amino-4-methyl-2-oxo-2H-chromen-3-yl)acetic acid;
2,3-Dihydro-1H-inden-5-yl(oxo)acetic acid; 3-(2-Pyridyl)aniline;
4-(3-Methyl-1H-1,2,4-triazol-5-yl)aniline; Benzidine;
(DL)-3-O-Methyldopa; Methyl
(2E)-3-(2-amino-5-methyl-3-pyridinyl)acrylate;
(5-Methylfuro[2,3-b]pyridin-2-yl)methanol;
(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethanaminium; R-phenylethyl
propionate; i-propyl benzoate; 4-Acetotoluide;
(1S)-1-(2,5-Dimethylphenyl)ethanaminium;
(1R)-2-Methyl-2,5-cyclohexadiene-1-carboxylic acid;
(2,2-Dimethoxyethyl)benzene; any suitable compounds including any
suitable combination of any suitable compounds and/or structures
(e.g., of one or more structures; etc.) included in Tables 5-8; and
pharmaceutically acceptable forms thereof; and/or salts of
thereof.
[0016] Additionally or alternatively, as shown in FIGS. 2-3,
embodiments of the method 100 (e.g., for identifying at least one
compound for treating a patient with a condition associated with at
least one of TMA, TMAO, and/or derivatives thereof; etc.) can
include determining one or more representative sequences (e.g.,
nucleic acid sequence; amino acid sequence; etc.) of one or more
targets (e.g., CutC enzymes; CntA enzymes; other enzymes; proteins;
other biological targets; non-biological targets; enzymes
associated with at least one of TMA, TMAO, and/or derivatives
thereof; etc.) S120, such as where the one or more representative
sequences are representative of one or more sets of sequences of
the one or more targets for at least one taxon of a set of
microorganism taxa (e.g., a representative sequence representative
of a plurality of sequences of the target from a plurality of
different taxa, such as from Firmicutes (phylum) and Proteobacteria
(phylum); etc.); generating one or more models (e.g., protein
structure models; etc.) of the one or more targets based on the one
or more representative sequences of the one or more targets S130;
determining one or more control binding parameters (and/or other
suitable interaction parameters; etc.) to the one or more targets
based on one or more experiments (e.g., control docking
simulations; other computational simulations; other experiments;
etc.) with the one or more models and one or more control molecules
(e.g., 3,3-dimethyl-1-butanol; L-carnitine; etc.) S140; determining
a set of compound binding parameters (and/or other suitable
interaction parameters; etc.) to the one or more targets based on a
set of experiments (e.g., control docking simulations; other
computational simulations; other experiments; etc.) with the one or
more models and a library of compounds (e.g., with the potential to
affect the one or more targets, such as the potential to inhibit
CutC enzymes and/or CntA enzymes; etc.) S150; identifying at least
one compound (e.g., from the library of compounds; etc.) for
treating the patient with the condition associated with the at
least one of TMA, TMAO, and derivatives thereof, based on a
comparison between one or more control binding parameters (and/or
other suitable interaction parameters associated with the one or
more control molecules; etc.) and the set of compound binding
parameters (and/or other suitable interaction parameters associated
with the compounds; etc.) S160; and/or validating one or more
compounds S170.
[0017] Embodiments of the method 100 and/or system 200 can function
to diagnose and/or treat one or more patients with one or more
conditions associated with at least one of TMA, TMAO, and/or
derivatives thereof, such as by using and/or administering (and/or
other suitable provision and/or promotion) of one or more compounds
affecting one or more targets (e.g., inhibiting CutC enzymes;
inhibiting CntA enzymes; etc.) associated with the one or more
conditions (e.g., correlated with, causative; etc.) and/or
associated with microorganisms from at least one taxon from a set
of taxa (e.g., from at least one of Firmicutes (phylum) and
Proteobacteria (phylum); etc.). Additionally or alternatively,
embodiments of the method 100 and/or system 200 can function to
identify one or more compounds that can be administered for
treating one or more patients with one or more conditions (e.g.,
associated with at least one of TMA, TMAO, and/or derivatives
thereof; etc.).
[0018] In an example, the method 100 can screen libraries of
compounds (e.g., including any suitable number of compounds; etc.),
based on molecular docking simulations, for identifying compounds
(e.g., drugs; etc.) that can bind the active site of one or more
targets (e.g., CutC enzymes; CntA enzymes; etc.) from
microorganisms (e.g., from Firmicutes (phylum) and/or
Proteobacteria (phylum); etc.) and associated with TMA, TMAO,
and/or derivatives thereof, such as for identifying compounds with
therapeutic effects (e.g., by inhibiting production of TMA; TMAO;
derivatives thereof; etc.) on conditions associated with TMA, TMAO,
and/or derivatives thereof. In an example, the method 100 can
overcome side effects and/or complications associated with
inhibiting FMO3 enzyme, such as by selectively inhibiting pathways
producing TMA, such as CutC/CutD and/or CntA/CntB.
[0019] Conditions (e.g., treatable by the one or more compounds;
etc.) preferably include conditions associated with
characterizations and/or therapies for one or more
microorganism-related conditions associated with at least one of
TMA, TMAO, and/or derivatives thereof (e.g., conditions
triggerable, caused by, correlated with, and/or otherwise
associated with one or more of TMA, TMAO, and/or derivatives
thereof, such as a high amounts of TMA, TMAO, and/or derivatives
thereof; etc.). Conditions associated with at least one of TMA,
TMAO, and/or derivatives thereof can include any one or more of:
cardiovascular conditions (e.g., atherosclerosis; severe heart
failure; coronary heart disease; inflammatory heart disease;
valvular heart disease; obesity; stroke; thrombosis, platelet
responsiveness, etc.); renal conditions (e.g., renal failure;
chronic kidney disease; polycystic kidney disease;
glomerulonephritis; IgA nephropathy; nephritis; nephrotic syndrome;
lupus; kidney cancer; rare kidney diseases; etc.);
metabolic-related conditions (e.g., trimethylaminuria (TMAU);
etc.); nutrition-related conditions (e.g., weight-related
conditions such as weight-loss conditions; blood sugar-related
conditions such as high blood sugar-related conditions;
allergy-related conditions such as allergies and/or intolerance
associated with wheat, gluten, dairy, soy, peanut, shellfish, tree
nut, egg; etc.).
[0020] Additionally or alternatively, conditions can include any
one or more of: gastrointestinal-related conditions (e.g.,
irritable bowel syndrome, inflammatory bowel disease, ulcerative
colitis, celiac disease, Crohn's disease, bloating, hemorrhoidal
disease, constipation, reflux, bloody stool, diarrhea, etc.);
skin-related conditions (e.g., acne, dermatomyositis, eczema,
rosacea, dry skin, psoriasis, dandruff, photosensitivity, rough
skin, itching, flaking, scaling, peeling, fine lines or cracks,
gray skin in individuals with dark skin, redness, deep cracks such
as cracks that can bleed and lead to infections, itching and
scaling of the skin in the scalp, oily skin such as irritated oily
skin, skin sensitivity to products such as hair care products,
imbalance in scalp microbiome, etc.); locomotor-related conditions
(e.g., gout, rheumatoid arthritis, osteoarthritis, reactive
arthritis, multiple sclerosis, Parkinson's disease, etc.);
cancer-related conditions (e.g., lymphoma; leukemia; blastoma; germ
cell tumor; carcinoma; sarcoma; breast cancer; prostate cancer;
basal cell cancer; skin cancer; colon cancer; lung cancer; cancer
conditions associated with any suitable physiological region;
etc.); anemia conditions; neurological-related conditions (e.g.,
ADHD, ADD, anxiety, Asperger's syndrome, autism, chronic fatigue
syndrome, depression, etc.); autoimmune-related conditions (e.g.,
Sprue, AIDS, Sjogren's, Lupus, etc.); endocrine-related conditions
(e.g., obesity, Graves' disease, Hashimoto's thyroiditis, metabolic
disease, Type I diabetes, Type II diabetes, etc.); Lyme disease
conditions; communication-related conditions; sleep-related
conditions; pain-related conditions; genetic-related conditions;
chronic disease; and/or any other suitable type of conditions.
Additionally or alternatively, conditions can include one or more
human behavior conditions which can include any one or more of:
caffeine consumption, alcohol consumption, other food item
consumption, dietary supplement consumption, probiotic-related
behaviors (e.g., consumption, avoidance, etc.), other dietary
behaviors, habituary behaviors (e.g., smoking; exercise conditions
such as low, moderate, and/or extreme exercise conditions; etc.),
menopause, other biological processes, social behavior, other
behaviors, and/or any other suitable human behavior conditions.
[0021] Conditions can include one or more of: diseases, symptoms,
causes (e.g., triggers, etc.), disorders, associated risk (e.g.,
propensity scores, etc.), associated severity, behaviors (e.g.,
caffeine consumption, habits, diets, etc.), and/or any other
suitable aspects associated with conditions. Conditions can be
associated with any suitable phenotypes (e.g., phenotypes
measurable for a human, animal, plant, fungi body, etc.).
[0022] In examples, the condition (e.g., one or more conditions;
etc.) can include at least one of: a cardiovascular condition
(e.g., atherosclerosis; etc.), a renal condition (e.g., renal
failure; etc.), a metabolic-related condition (e.g.,
trimethylaminuria; etc.), and/or a nutrition-related condition
(e.g., a weight-related condition; a high blood sugar-related
condition; etc.); where the condition can be associated with at
least one of TMA, TMAO, and/or derivatives thereof; and where
administering to one or more patients can include administering, to
the one or more patients with the one or more conditions (e.g.,
etc.;), a therapeutically effective amount of one or more compounds
(e.g., any suitable compounds in and/or including any suitable
combination of compounds from Tables 1-8; etc.) for inhibiting one
or more enzymes (e.g., CutC enzymes; CntA enzymes; enzymes
associated with the at least one of TMA, TMAO, and/or derivatives
thereof; etc.) of microorganisms from at least one of Firmicutes
(phylum) and/or Proteobacteria (phylum).
[0023] Additionally or alternatively, data described herein (e.g.,
binding parameters; interaction parameters; identified compounds;
outputs from models and/or experiments; etc.) can be associated
with any suitable temporal indicators (e.g., seconds, minutes,
hours, days, weeks, time periods, time points, timestamps, etc.)
including one or more: temporal indicators indicating when the data
was collected, determined, transmitted, received, and/or otherwise
processed; temporal indicators providing context to content
described by the data; changes in temporal indicators (e.g., data
over time; change in data; data patterns; data trends; data
extrapolation and/or other prediction; etc.); and/or any other
suitable indicators related to time.
[0024] Additionally or alternatively, parameters, metrics, inputs,
outputs, and/or other suitable data can be associated with value
types including any one or more of: scores (e.g., binding
parameters; interaction parameters; etc.), binary values (e.g.,
presence of a target within a microorganism taxon; etc.),
classifications (e.g., taxon classifications; etc.), confidence
levels, identifiers (e.g., compound identifiers; etc.), values
along a spectrum, and/or any other suitable types of values. Any
suitable types of data described herein can be used as inputs
(e.g., for different models described herein; for portions of
embodiments the method 100; etc.), generated as outputs (e.g., of
models), and/or manipulated in any suitable manner for any suitable
components associated with embodiments of the method 100 and/or
system 200.
[0025] One or more instances and/or portions of embodiments of the
method 100 and/or processes described herein can be performed
asynchronously (e.g., sequentially), concurrently (e.g., in
parallel; concurrently on different threads for parallel computing
to improve system processing ability for screening and/or otherwise
determining compounds; etc.), in temporal relation to a trigger
event (e.g., performance of a portion of the method 100), and/or in
any other suitable order at any suitable time and frequency by
and/or using one or more instances of embodiments of the system
200, components, and/or entities described herein.
[0026] Embodiments of the system 200 can include any one or more
of: compounds and/or pharmaceutically acceptable forms thereof,
and/or salts (e.g., pharmaceutically acceptable salts; etc.)
thereof; computing systems (e.g., for identifying one or more
compounds; etc.); sample handling networks; sequencing systems;
and/or any other suitable components. The system 200 and/or
portions of the system 200 can entirely or partially be executed
by, hosted on, communicate with, and/or otherwise include: a remote
computing system (e.g., a server, at least one networked computing
system, stateless, stateful; etc.), a local computing system, a
user device (e.g., mobile phone device, other mobile device,
personal computing device, tablet, wearable, head-mounted wearable
computing device, wrist-mounted wearable computing device, etc.), a
care provider device, databases, application programming interfaces
(APIs) (e.g., for accessing data described herein, etc.) and/or any
suitable components. Communication by and/or between any components
of the system 200 can include wireless communication (e.g., WiFi,
Bluetooth, radiofrequency, Zigbee, Z-wave, etc.), wired
communication, and/or any other suitable types of communication.
The components of the system 200 can be physically and/or logically
integrated in any manner (e.g., with any suitable distributions of
functionality across the components, such as in relation to
portions of embodiments of the method 100; etc.).
[0027] Portions of embodiments of the method 100 and/or system 200
can be performed by any one or more of: first parties; third
parties; car providers (e.g., doctors; nurses; etc.); lab
technicians; users; compound providers; and/or any suitable
entities.
[0028] However, embodiments of the method 100 and/or system 200 can
be configured in any suitable manner.
2.1 Administering a Compound.
[0029] Embodiments of the method 100 can include administering
(and/or other suitable provision of; promotion of; etc.)
administering one or more compounds (e.g., a therapeutically
effective amount of the one or more compounds; etc.) to one or more
patients with one or more conditions Silo (e.g., one or more
conditions associated with the at least one of TMA, TMAO, and/or
derivatives thereof; etc.), which can function to facilitate
treatment of one or more patients.
[0030] A therapeutically effective amount of the one or more
compounds is preferably administered, but any suitable amounts of
the one or more compounds can be administered.
[0031] The compounds (e.g., drugs; molecules; etc.) preferably
affect (e.g., inhibiting; etc.) one or more targets (e.g., CutC
enzymes; CntA enzymes; etc.) associated with one or more conditions
associated at least one of TMA, TMAO, and/or derivatives thereof,
such as for inhibiting production of TMA, TMAO, and/or derivatives
thereof (e.g., for preventing, treating, and/or reducing the effect
of conditions associated with TMA, TMAO, and/or derivatives
thereof; etc.). Additionally or alternatively, the compounds can
otherwise affect (e.g., activate, upregulate, downregulate, bind;
etc.) the one or more targets, and/or the targets can be associated
with any suitable conditions. Compounds can include any suitable
combination of (e.g., one or more; combinations; individual
molecules and/or compounds; etc.), derivative of, pharmaceutically
acceptable form of, and/or any suitable form of compounds included
in Tables 1-8.
[0032] Compounds can include any suitable pharmaceutically
acceptable forms of the compounds, which can include any one or
more of: derivatives; pharmaceutically deliverable forms; forms
with carriers, agents, supplemental components; salts; and/or any
suitable acceptable forms. Compounds can include any suitable salts
(e.g., pharmaceutically acceptable salts; etc.) thereof, and/or any
suitable forms of the compounds.
[0033] Targets (e.g., targets targeted by the one or more
compounds; targets causing, contributing to, with therapeutic
effect in relation to, correlated with, and/or otherwise associated
with one or more conditions etc.) can include any one or more of:
CutC enzymes; CntA enzymes; CutD enzymes; CntB enzymes; other
enzymes (e.g., associated with at least one of TMA, TMAO, and/or
derivatives thereof; etc.); proteins; target markers (e.g.,
biomarkers; etc.); targets of interest; known or identified
targets; unknown or previously unidentified targets; genetic
targets; sequences (e.g., amino acid sequences; nucleic acid
sequences; etc.); compounds; peptides; carbohydrates; lipids;
nucleic acids; cells (e.g., whole cells, etc.); metabolites;
natural products; diagnostic biomarkers; prognostic biomarkers;
predictive biomarkers; other molecular biomarkers; biological
targets; non-biological targets; other molecules (e.g., associated
with at least one of TMA, TMAO, and/or derivatives thereof; etc.);
and/or any other suitable targets.
[0034] Targets are preferably associated with microorganisms (e.g.,
are from the microorganisms; are produced by the microorganisms;
have been found in relation to the microorganisms; are present in
the microorganisms; are encoded by genetic sequences, amino acid
sequences, and/or other suitable sequences of the microorganisms;
etc.) from at least one taxon from a set of microorganism taxa
(e.g., from at least one of Firmicutes (phylum) and Proteobacteria
(phylum); etc.). Additionally or alternatively, targets can be
associated with microorganisms from any suitable microorganism taxa
(e.g., domain, kingdom, phylum, class, order, family, genus,
species; etc.) and/or microorganisms associated with any suitable
body site including any one or more of gut, skin, nose, mouth,
genitals, and/or any suitable body site. Administering a compound
can include any one or more of providing, promoting, and/or
otherwise administering a compound.
[0035] Administering one or more compounds can include
administering (e.g., a therapeutically effective amount of; etc.)
one or more compounds for inhibiting (and/or otherwise affecting)
CutC enzymes, such as CutC enzymes of microorganisms from at least
one of Firmicutes (phylum), Proteobacteria (phylum), and/or other
suitable taxa.
[0036] Compounds for inhibiting (and/or otherwise affecting) CutC
enzymes (e.g., associated with microorganisms from at least one of
Proteobacteria and Firmicutes; etc.) can include one or more
3,3-dimethyl-1-butanol (DMB) analogues (e.g., binding with equal or
higher affinity to CutC enzymes than DMB, such as for CutC enzymes
belonging to Proteobacteria and/or Firmicutes; etc.). In examples,
DMB can inhibit TMA formation by CutC enzymes (e.g., derived from
cultured microbes in a non-lethal way, such as not an antibiotic);
can reduce TMAO levels (e.g., in animals with a high choline or
carnitine diet; etc.); and/or can bind the active site of CutC
enzymes (e.g., with higher affinity than choline, thereby exerting
competitive inhibition; etc.). In examples, DMB analogues (and/or
compounds generally) can include any one or more compounds included
in Table 1.
TABLE-US-00001 TABLE 1 Examples of Analogues of DMB that can Bind
CutC Enzymes of Microorganisms from Proteobacteria and/or
Firmicutes. Binding Binding Energy Energy (to CutC (to CutC IUPAC
enzyme, enzyme, Structure SMILES code nomenclature Proteobacteria)
Firmicutes) ##STR00001## CCC(CC)CO 2-Ethyl-1- butanol -4.9 kcal/mol
##STR00002## CC(C)(C)[C@](CO)O (2R)-3,3- Dimethyl- 1,2- butanediol
-5.5 kcal/mol -5.2 kcal/mol ##STR00003## CC(C)(C)[C@@H](CO)O
(2S)-3,3- Dimethyl- 1,2- butanediol -5.4 kcal/mol -5.2 kcal/mol
##STR00004## C[C@@H](CC(C)C)O (2S)-4- Methyl-2- pentanol -5.2
kcal/mol ##STR00005## C[C@@H](C(C)C)O (2S)-3- Methyl-2- butanol
-4.8 kcal/mol ##STR00006## C[C@H](CC(C)C)O (2R)-4- Methyl-2-
pentanol -5.0 kcal/mol ##STR00007## C[C@H](C(C)C)O (2R)-3-
Methyl-2- butanol -4.8 kcal/mol ##STR00008## CCC[C@H](C)O (2S)-2-
Pentanol -4.8 kcal/mol ##STR00009## C[C@@H](CCO)CO (2S)-2-
Methyl-1,4- butanediol -4.9 kcal/mol -5.0 kcal/mol ##STR00010##
CC(C)(CCO)O 2-Methyl- 2,4- butanediol -4.9 kcal/mol -5.1 kcal/mol
##STR00011## CCC(CO)(CO)CO Trimethylol propane -5.2 kcal/mol -5.3
kcal/mol
[0037] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound including a 3,3-dimethyl-1-butanol (DMB) analogue
including at least one (e.g., any one or more; etc.) of:
2-Ethyl-1-butanol; (2R)-3,3-Dimethyl-1,2-butanediol;
(2S)-3,3-Dimethyl-1,2-butanediol; (2S)-4-Methyl-2-pentanol;
(2S)-3-Methyl-2-butanol; (2R)-4-Methyl-2-pentanol;
(2R)-3-Methyl-2-butanol; (2S)-2-Pentanol;
(2S)-2-Methyl-1,4-butanediol; 2-Methyl-2,4-butanediol;
Trimethylolpropane; and pharmaceutically acceptable forms thereof
(e.g., derivatives thereof; pharmaceutically deliverable forms
thereof; etc.); and/or salts (e.g., pharmaceutically acceptable
salts; etc.) thereof. However, compounds including a
3,3-dimethyl-1-butanol (DMB) analogue can be configured in any
suitable manner, and administering such compounds can be performed
in any suitable manner (e.g., for affecting any suitable
targets).
[0038] Compounds for inhibiting (and/or otherwise affecting) CutC
enzymes can include one or more compounds for inhibiting the CutC
enzymes of microorganisms from Firmicutes (phylum), such as where
the one or more compounds (and/or compounds generally) can include
any one or more compounds included in Table 2 (e.g., where the
compounds can include specificity for CutC enzymes from
microorganisms from Firmicutes; where the compounds do not bind or
bind with lower affinity to CutC enzymes from microorganisms from
Proteobacteria; where each compound can be representative of a
subset of molecules exerting the same binding energy and such as
with similar structure to the compound; where the compounds can
include higher affinity, as indicated by the binding energy values,
than choline or DMB, to the CutC enzymes; etc.).
TABLE-US-00002 TABLE 2 Examples of Compounds (e.g., molecules) that
can Bind CutC Enzymes of Microorganisms from Firmicutes (e.g.,
Firmicutes-CoD.sub.5P1 CutC Enzyme) Binding Energy (to CutC IUPAC
enzyme, Structure SMILES code nomenclature Firmicutes) ##STR00012##
COc1ccc(cc1)CCC.dbd.O 3-(4- Methoxyphenyl)propanal -4.9 kcal/mol
##STR00013## C[C@H](Cc1cccnc1)[NH3+] 1-(3-Pyridinyl)-2- propanamine
-5.0 kcal/mol ##STR00014## CC[C@@H](C)c1ccccc1O 2-[(2R)-2-
Butanyl]phenol -5.2 kcal/mol ##STR00015## CCCc1ccc(cc1)C(.dbd.O)O
4-Propylbenzoic acid -5.3 kcal/mol ##STR00016##
C[C@@H](COCc1ccccc1)O (2S)-1- (Benzyloxy)-2- propanol -5.4 kcal/mol
##STR00017## COC(.dbd.O)CCc1ccc(cc1)O Methyl 3-(4-
hydroxyphenyl)propanoate -5.5 kcal/mol ##STR00018##
C[C@@](Cc1ccccc1)(C(.dbd.O)O)[NH3+] .alpha.- Methylphenyialanine
-5.6 kcal/mol ##STR00019## CC(C)(C)C(c1ccccc1)O 2,2-Dimethyl-1-
phenyl-1- propanol -5.7 kcal/mol ##STR00020##
COC(.dbd.O)[C@@H](c1ccccc1)O Methyl (2R)- hydroxy(phenyl)acetate
-5.8 kcal/mol ##STR00021## c1ccc(cc1)[C@@H]1CCC[NH2+]1 (2S)-2-
Phenylpyrrolidinium -5.9 kcal/mol ##STR00022## Cc1c(noc1N)c1ccccc1
4-Methyl-3- phenyl-1,2- oxazol-5-amine -6.0 kcal/mol ##STR00023##
c1cc(ccc1c1ccc(cc1)N)N 4,4'- Biphenyldiamine -6.1 kcal/mol
##STR00024## Cc1ccc(cc1)c1ccccc1C#N 4'-Methyl-2-
biphenylcarbonitrile -6.2 kcal/mol ##STR00025##
c1ccc(cc1)c1ccc(cc1)O 4-Biphenylol -6.3 kcal/mol ##STR00026##
Cc1ccc(cc1)c1cc(on1)CCO 2-[3-(4- Methylphenyl)-1,2-
oxazol-5-yl]ethanol -6.4 kcal/mol ##STR00027##
c1ccc(cc1)c1ccc(cc1)C(.dbd.O)N 4- Biphenylcarboxamide -6.5 kcal/mol
##STR00028## C#Cc1ccc(cc1)c1ccccc1 4- Ethynylbiphenyl -6.6 kcal/mol
##STR00029## Cc1ccc(cc1)c1nc([nH]n1)N 5-(4-Methylphenyl)-
1H-1,2,4-triazol- 3-amine -6.7 kcal/mol ##STR00030##
Cc1ccc(cc1)c1cc([nH]n1)N 5-(4- Methylphenyl)- 1H-pyrazol-3-amine
-6.8 kcal/mol ##STR00031## c1cc(c(cc1O)O)O 4- Hydroxycatechol -6.9
kcal/mol ##STR00032## c1ccc(cc1)c1cc(n[nH]1)C(.dbd.O)NN
3-Phenyl-1H- pyrazole-5- carbohydrazide -7.0 kcal/mol ##STR00033##
Cc1ccc(cc1O)O 4- Methyl-1,3- benzenediol -7.1 kcal/mol
[0039] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CutC enzymes of the microorganisms from
Firmicutes (phylum), where the compound includes at least one
(e.g., any one or more; etc.) of: 3-(4-Methoxyphenyl)propanal;
1-(3-Pyridinyl)-2-propanamine; 2-[(2R)-2-Butanyl]phenol;
4-Propylbenzoic acid; (2S)-1-(Benzyloxy)-2-propanol; Methyl
3-(4-hydroxyphenyl)propanoate; .alpha.-Methylphenylalanine;
2,2-Dimethyl-1-phenyl-1-propanol; Methyl
(2R)-hydroxy(phenyl)acetate; (2S)-2-Phenylpyrrolidinium;
4-Methyl-3-phenyl-1,2-oxazol-5-amine; 4,4'-Biphenyldiamine;
4'-Methyl-2-biphenylcarbonitrile; 4-Biphenylol;
2-[3-(4-Methylphenyl)-1,2-oxazol-5-yl]ethanol;
4-Biphenylcarboxamide; 4-Ethynylbiphenyl;
5-(4-Methylphenyl)-1H-1,2,4-triazol-3-amine;
5-(4-Methylphenyl)-1H-pyrazol-3-amine; 4-Hydroxycatechol;
3-Phenyl-1H-pyrazole-5-carbohydrazide; 4-Methyl-1,3-benzenediol;
and pharmaceutically acceptable forms thereof (e.g., derivatives
thereof; pharmaceutically deliverable forms thereof; etc.); and/or
salts (e.g., pharmaceutically acceptable salts; etc.) thereof.
However, compounds for inhibiting CutC enzymes of microorganisms
from Firmicutes (phylum) can be configured in any suitable manner,
and administering such compounds can be performed in any suitable
manner (e.g., for affecting any suitable targets).
[0040] Compounds for inhibiting (and/or otherwise affecting) CutC
enzymes can include one or more compounds for inhibiting the CutC
enzymes of microorganisms from Proteobacteria (phylum), such as
where the one or more compounds (and/or compounds generally) can
include any one or more compounds included in Table 3 (e.g., where
the compounds can include specificity for CutC enzymes from
microorganisms from Proteobacteria; where the compounds do not bind
or bind with lower affinity to CutC enzymes from microorganisms
from Firmicutes; where each compound can be representative of a
subset of molecules exerting the same binding energy and such as
with similar structure to the compound; where the compounds can
include higher affinity, as indicated by the binding energy values,
than choline or DMB, to the CutC enzymes; etc.).
TABLE-US-00003 TABLE 3 Examples of Compounds (e.g., molecules) that
can Bind CutC Enzymes of Microorganisms from Proteobacteria (e.g.,
Proteobacteria-B4EYG1 CutC Enzyme) Binding Energy (to CutC IUPAC
enzyme, Structure SMILES code nomenclature Proteobacteria)
##STR00034## C(C[NH3+])C[NH2+]CCO N-(2- Hydroxyethyl)- 1,3-
propanediaminium -4.8 kcal/mol ##STR00035## CC(C)(CCO)OC
3-Methoxy-3- methylbutanol -4.9 kcal/mol ##STR00036##
c1cnccc1C[NH3+] 4- Pyridinyl- methanaminium -5.0 kcal/mol
##STR00037## CNc1cccnc1 N-Methyl-3- pyridinamine -5.1 kcal/mol
##STR00038## COc1ccccn1 2- Methoxypyridine -5.2 kcal/mol
##STR00039## Cc1cc(cnc1)N 5-Methyl-3- pyridinamine -5.3 kcal/mol
##STR00040## Cc1ccncc1C[NH3+] 1-(4-Methyl-3- pyridinyl) methanamine
-5.4 kcal/mol ##STR00041## Cc1cc(cc(c1)C)C Mesitylene -5.5 kcal/mol
##STR00042## c1ccc(cc1)/C.dbd.NO (E)-Benzaldoxime -5.6 kcal/mol
##STR00043## CC(C)[C@H](C(C)(C)CO)O (3R)-2,2,4- Trimethyl-1,3-
pentanediol -5.7 kcal/mol ##STR00044##
C1C[C@@H]2C[C@H]1C[N@@H+]2CC(.dbd.O)O (1R,4R)-2- Azabicyclo[2.2.1]
hept-2-ylacetic acid -5.8 kcal/mol ##STR00045##
CC(.dbd.O)c1cccc(c1)O 3- ACETYLPHENOL -5.9 kcal/mol ##STR00046##
c1cc(cc(c1)O)C(.dbd.O)O 3- Hydroxy- benzoicacid -6.0 kcal/mol
##STR00047## c1cc2cc[nH]c2c(c1)CO 1H-Indol-7- ylmethanol -6.1
kcal/mol ##STR00048## C.dbd.Cc1cccc(c1)N 3-Vinylaniline -6.2
kcal/mol ##STR00049##
C1[C@H]2C[C@H]3C[C@@H]1C[C@@](C2)(C3)N.dbd.C.dbd.O (3s,5s,7s)-1-
Isocyanato- adamantane -6.3 kcal/mol ##STR00050##
C[C@@]1([C@@H]2C[C@@H](C2(C)C)CC1.dbd.O)O (1R,2S,5R)-2-
Hydroxy-2,6,6- trimethylbicyclo [3.1.1]heptan-3- one -6.4 kcal/mol
##STR00051## CC1([C@H]2CCC(.dbd.C[C@@H]1C2)C (-)-.beta.-Pinene -6.5
kcal/mol ##STR00052## c1ccc2c(c1)c([nH]c2N)N 2H-Isoindole-1,3-
diamine -6.6 kcal/mol ##STR00053##
C1[C@H]2C[C@H]3C[C@@H]1C[C@@](C2)(C3)O (3s,5s,7s)-1- Adamantanol
-6.7 kcal/mol ##STR00054## C1C[C@H]2C[C@@H]1[C@H]([C@H]2[NH3+])CO
(3- Aminobicyclo [2.2.1]hept-2- yl)methanol -6.8 kcal/mol
##STR00055## c1cc(cc(c1)O)CN[NH3+] 3- (Hydrazinomethyl) phenol -6.9
kcal/mol ##STR00056## C1CC[C@@H]([C@@H](C1)C(.dbd.O)N)[NH3+]
(1S,2R)-2- Carbamoylcyclo- hexanaminium -7.0 kcal/mol ##STR00057##
C[C@]12CC[C@H](C1)C(C2.dbd.O)(C)C (1S,4R)-1,3,3- Trimethylbicyclo
[2.2.1]heptan-2- one -7.1 kcal/mol ##STR00058##
C[C@@]12CC[C@@H](C1)C(C2.dbd.O)(C)C (1R,4S)-1,3,3- Trimethylbicyclo
[2.2.1]heptan-2- one -7.4 kcal/mol
[0041] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CutC enzymes of the microorganisms from
Proteobacteria (phylum), where the compound includes at least one
(e.g., any one or more; etc.) of:
N-(2-Hydroxyethyl)-1,3-propanediaminium; 3-Methoxy-3-methylbutanol;
4-Pyridinylmethanaminium; N-Methyl-3-pyridinamine;
2-Methoxypyridine; 5-Methyl-3-pyridinamine;
1-(4-Methyl-3-pyridinyl)methanamine; Mesitylene; (E)-Benzaldoxime`
(3R)-2,2,4-Trimethyl-1,3-pentanediol;
(1R,4R)-2-Azabicyclo[2.2.1]hept-2-ylacetic acid; 3-ACETYLPHENOL;
3-Hydroxybenzoicacid; 1H-Indol-7-ylmethanol; 3-Vinylaniline;
(3s,5s,7s)-1-Isocyanatoadamantane;
(1R,2S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one;
(-)-.beta.-Pinene; 2H-Isoindole-1,3-diamine;
(3s,5s,7s)-1-Adamantanol; (3-Aminobicyclo[2.2.1]hept-2-yl)methanol;
3-(Hydrazinomethyl)phenol; (1S,2R)-2-Carbamoylcyclohexanaminium;
(1S,4R)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one;
(1R,4S)-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one; and
pharmaceutically acceptable forms thereof (e.g., derivatives
thereof; pharmaceutically deliverable forms thereof; etc.); and/or
salts (e.g., pharmaceutically acceptable salts; etc.) thereof.
However, compounds for inhibiting CutC enzymes of microorganisms
from Proteobacteria (phylum) can be configured in any suitable
manner, and administering such compounds can be performed in any
suitable manner (e.g., for affecting any suitable targets).
[0042] Compounds for inhibiting (and/or otherwise affecting) CutC
enzymes can include one or more compounds for inhibiting the CutC
enzymes of microorganisms from Firmicutes (phylum) and
Proteobacteria (phylum) (e.g., inhibiting CutC enzymes of first
microorganisms from Firmicutes as well as CutC enzymes of second
microorganisms from Proteobacteria, etc.), such as where the one or
more compounds (and/or compounds generally) can include any one or
more compounds included in Table 4 (e.g., compounds binding CutC
enzymes associated with Firmicutes, and binding CutC enzymes
associated with Proteobacteria; such as where the compounds can
inhibit products of TMA by CutC in a set of microorganisms across
different taxa, such as across Firmicutes and Proteobacteria; where
each compound can be representative of a subset of molecules
exerting the same binding energy and such as with similar structure
to the compound; where the compounds can include higher affinity,
as indicated by the binding energy values, than choline or DMB, to
the CutC enzymes; etc.).
TABLE-US-00004 TABLE 4 Examples of Compounds (e.g., molecules) that
can Bind CutC Enzymes of Microorganisms from Proteobacteria and
Firmicutes Binding Binding Energy Energy (to CutC (to CutC IUPAC
enzyme, enzyme, Structure SMILES code nomenclature Proteobacteria)
Firmicutes) ##STR00059## CC1(CC[NH2+]CC1)C(.dbd.O)OC Methyl
4-methyl- 4- piperidine- carboxylate -4.8 kcal/mol -4.8 kcal/mol
##STR00060## CCCCCCC(.dbd.O)OC Methyl heptanoate -4.9 kcal/mol -4.9
kcal/mol ##STR00061## Cc1cccnn1 3- Methylpyridazine -5.0 kcal/mol
-5.0 kcal/mol ##STR00062## Cc1c(onc1N)C 4,5-Dimethyl-1,2-
oxazol-3-amine -5.1 kcal/mol -5.1 kcal/mol ##STR00063##
c1ccc(c(c1)O)OCCO 2-(2- Hydroxyethoxy) phenol -5.2 kcal/mol -5.2
kcal/mol ##STR00064## c1cc(cnc1)C[NH2+]CCO 2-Hydroxy-N-(3-
pyridinylmethyl) ethanaminium -5.3 kcal/mol -5.3 kcal/mol
##STR00065## c1ccc(cc1)CCCO 3-Phenyl-1- propanol -5.4 kcal/mol -5.4
kcal/mol ##STR00066## C[C@H](CCCC(C)C)O (2R)-6-Methyl-2- heptanol
-5.5 kcal/mol -5.5 kcal/mol ##STR00067## c1ccc(cc1)OCC(.dbd.O)NN 2-
Phenoxy- acetohydrazide -5.6 kcal/mol -5.6 kcal/mol ##STR00068##
CCCCCCCC(.dbd.O)NO N- Hydroxyoctanamid -5.7 kcal/mol -5.7 kcal/mol
##STR00069## C1CC(C1)C(.dbd.O)NN Cyclobutane- carbohydrazide -5.8
kcal/mol -5.8 kcal/mol ##STR00070## c1ccc(cc1)NN Phenylhydrazine
-5.9 kcal/mol -5.9 kcal/mol ##STR00071##
C1[C@@H]2C.dbd.C[C@H]1NC2.dbd.O (1S,4R)-2- Azabicyclo[2.2.1]
hept-5-en-3-one -6.0 kcal/mol -6.0 kcal/mol ##STR00072##
c1ccc(c(c1)C(.dbd.O)N)O salicylamide -6.1 kcal/mol -6.1 kcal/mol
##STR00073## C1[C@@H]2C[C@@H]3C[C@H]1C[C@H](C2)C3 Adamantane -6.2
kcal/mol -6.2 kcal/mol ##STR00074## C1C[C@@H]2C[C@H](C1)C[NH2+]C2
3- Azabicyclo [3.3.1]nonane -6.4 kcal/mol -6.4 kcal/mol
##STR00075## Cc1ccccc1/C(.dbd.N/O)/N N-Hydroxy-2- methylbenzene-
carboximidamide -6.5 kcal/mol -4.9 kcal/mol ##STR00076##
CC1([C@H]2CC[C@H](C2)C1.dbd.C)C (-)-camphene -6.6 kcal/mol -5.4
kcal/mol ##STR00077## C1[C@H]2C[C@@H]([C@@H]1C.dbd.C2)CO
(1S,2S,4S)- Bicyclo[2.2.1]hept- 5-en-2-ylmethanol -6.7 kcal/mol
-6.1 kcal/mol ##STR00078##
C1C.dbd.C[C@H]2[C@H]1[C@H]1C[C@@H]2C.dbd.C1 Dicyclopentadiene -6.8
kcal/mol -5.0 kcal/mol ##STR00079##
C1C[C@H]2C[NH2+]C[C@@H]1[C@@H]2O (8-anti)-3- Azabicyclo[3.2.1]
octan-8-ol -5.8 kcal/mol -6.9 kcal/mol ##STR00080##
C1C.dbd.C[C@@H]2[C@H]1[C@H]1C[C@@H]2C.dbd.C1 (1R,2S,6R,7S)-
Tricyclo[5.2.1.02,6] deca-3,8-diene -7.0 kcal/mol -6.0 kcal/mol
[0043] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CutC enzymes of the microorganisms from
Firmicutes (phylum) and Proteobacteria (phylum), where the compound
includes at least one (e.g., any one or more; etc.) of: Methyl
4-methyl-4-piperidinecarboxylate; Methyl heptanoate;
3-Methylpyridazine; 4,5-Dimethyl-1,2-oxazol-3-amine;
2-(2-Hydroxyethoxy)phenol;
2-Hydroxy-N-(3-pyridinylmethyl)ethanaminium; 3-Phenyl-1-propanol;
(2R)-6-Methyl-2-heptanol; 2-Phenoxyacetohydrazide;
N-Hydroxyoctanamid; Cyclobutanecarbohydrazide; Phenylhydrazine;
(1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one; salicylamide;
Adamantane; 3-Azabicyclo[3.3.1]nonane;
N-Hydroxy-2-methylbenzenecarboximidamide; (-)-camphene;
(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethanol; Dicyclopentadiene;
(8-anti)-3-Azabicyclo[3.2.1]octan-8-ol;
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6]deca-3,8-diene; and
pharmaceutically acceptable forms thereof (e.g., derivatives
thereof; pharmaceutically deliverable forms thereof; etc.); and/or
salts (e.g., pharmaceutically acceptable salts; etc.) thereof. In
an example, compounds including different binding affinities
(and/or other suitable interaction parameters) to CutC enzymes
depending on the association of the CutC enzyme to a given taxon
(e.g., CutC enzymes of microorganisms from Proteobacteria; CutC
enzymes of microorganisms from Firmicutes; etc.), and/or compounds
with different affinities generally, can enable different
applications, such as where a compound with high affinity can exert
an irreversible inhibition on the CutC enzyme. However, compounds
for inhibiting CutC enzymes of microorganisms from Firmicutes
(phylum) and Proteobacteria (phylum) can be configured in any
suitable manner, and administering such compounds can be performed
in any suitable manner (e.g., for affecting any suitable
targets).
[0044] Administering one or more compounds can include
administering (e.g., a therapeutically effective amount of; etc.)
one or more compounds for inhibiting (and/or otherwise affecting)
CntA enzymes, such as CntA enzymes of microorganisms from at least
one of Firmicutes (phylum), Proteobacteria (phylum), and/or other
suitable taxa. In examples, L-carnitine (e.g., a substrate for CntA
enzymes; etc.) can facilitate the production of TMA, TMAO, and/or
derivatives thereof through binding to an active site on CntA
enzymes, and where L-carnitine can be associated with (e.g., cause,
correlated with, influence, etc.) metabolic-related conditions,
nutritional-related conditions (e.g., weight-related conditions;
high blood sugar-related conditions; etc.), and/or other suitable
conditions, such as where compounds inhibiting (and/or otherwise
affecting) CntA enzymes can decrease the effect of L-carnitine
and/or CntA enzymes in relation to the one or more conditions.
[0045] Compounds for inhibiting (and/or otherwise affecting) CntA
enzymes (e.g., associated with microorganisms from at least one of
Proteobacteria and Firmicutes; etc.) can include one or more
L-carnitine analogues (e.g., binding with equal or higher affinity
to CntA enzymes than L-carnitine, such as for CntA enzymes
belonging to Proteobacteria and/or Firmicutes; etc.). In examples,
the L-carnitine analogues and/or other suitable compounds can bind
to CntA enzymes to competitively inhibit the binding of L-carnitine
to the CntA enzymes (e.g., where the substrate and inhibitor cannot
bind the active site simultaneously; where the competitive
inhibition can facilitate decrease in production of TMA, TMAO,
and/or derivatives thereof; etc.). In examples, L-carnitine
analogues (and/or compounds generally) can include any one or more
compounds included in Table 5. Table 5.
TABLE-US-00005 TABLE 5 Examples of Analogues of L-carnitine that
can Bind CntA Enzymes of Microorganisms from Proteobacteria and/or
Firmicutes. Binding Energy Binding Energy IUPAC (to CntA enzyme,
(to CntA enzyme, Structure SMILES code nomenclature Proteobacteria)
Firmicutes) ##STR00081## C[NH2+][C@@H](CCC(.dbd.O)O)C(.dbd.O)O N-
Methylglutamic acid -4.9 kcal/mol ##STR00082##
C1CC[NH+](C1)CCCC(.dbd.O)O 4-(1- Pyrrolidinyl) butanoic acid -5.1
kcal/mol ##STR00083## CC1(CC[NH2+]CC1)C(.dbd.O)O 4-Methyl-4-
piperidinecarboxylic acid -4.7 kcal/mol -5.0 kcal/mol ##STR00084##
C1C[NH2+]CCC1C(.dbd.O)O Isonipecotic acid -4.9 kcal/mol
[0046] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound including an L-carnitine analogue including at least one
(e.g., any one or more; etc.) of: N-Methylglutamic acid;
4-(1-Pyrrolidinyl)butanoic acid; 4-Methyl-4-piperidinecarboxylic
acid; Isonipecotic acid; and pharmaceutically acceptable forms
thereof (e.g., derivatives thereof; pharmaceutically deliverable
forms thereof; etc.); and/or salts (e.g., pharmaceutically
acceptable salts; etc.) thereof. However, compounds including an
L-carnitine analogue can be configured in any suitable manner, and
administering such compounds can be performed in any suitable
manner (e.g., for affecting any suitable targets).
[0047] Compounds for inhibiting (and/or otherwise affecting) CntA
enzymes can include one or more compounds for inhibiting the CntA
enzymes of microorganisms from Firmicutes (phylum), such as where
the one or more compounds (and/or compounds generally) can include
any one or more compounds included in Table 6 (e.g., where the
compounds can include specificity for CntA enzymes from
microorganisms from Firmicutes; where the compounds do not bind or
bind with lower affinity to CntA enzymes from microorganisms from
Proteobacteria; where each compound can be representative of a
subset of molecules exerting the same binding energy and such as
with similar structure to the compound; where the compounds can
include higher affinity, as indicated by the binding energy values,
than L-carnitine, to the CntA enzymes; etc.).
TABLE-US-00006 TABLE 6 Examples of Compounds (e.g., molecules) that
can Bind CntA Enzymes of Microorganisms from Firmicutes (e.g.,
Firmicutes-J3B3E2 CntA Enzyme) Binding Energy IUPAC (to CntA
enzyme, Structure SMILES code nomenclature Firmicutes) ##STR00085##
CCCc1ccccc1 N-propylbenzene -5.8 kcal/mol ##STR00086##
CCNc1cccc[nH+]1 N-Ethyl-2- pyridinamine -5.7 kcal/mol ##STR00087##
CCCN1C[C@H](CC1.dbd.O)[NH3+] (4R)-4-Amino-1- propyl-2-
pyrrolidinone -5.6 kcal/mol ##STR00088## Cc1cc(ccc1N)N 2,5-
Diaminotoluene -5.5 kcal/mol ##STR00089## CCOc1ccccc1 Ethyl phenyl
ether -5.4 kcal/mol ##STR00090## c1ccc(cc1)OC#N Phenylcyanate -5.3
kcal/mol ##STR00091## CC(.dbd.O)C[C@@H]1CCC.dbd.C1
1-(2-Cyclopenten- 1-yl)acetone -5.2 kcal/mol ##STR00092##
Cc1ccc[nH+]c1N 2-Amino-3- methylpyridinium -5.1 kcal/mol
##STR00093## c1cc(cnc1)/C.dbd.N/O E-pyridine-3- aldoxime -5.0
kcal/mol ##STR00094## C1CCC(CC1)NC.dbd.O N- Cyclohexylformamide
-4.9 kcal/mol ##STR00095## CCC/C.dbd.C(\C)/C(.dbd.O)O 2-Methyl-2-
hexenoic acid -4.8 kcal/mol ##STR00096## CCCC(CCC)[NH3+] 4-
Heptanaminium -4.7 kcal/mol
[0048] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CntA enzymes of the microorganisms from
Firmicutes (phylum), where the compound includes at least one
(e.g., any one or more; etc.) of: N-propylbenzene;
N-Ethyl-2-pyridinamine; (4R)-4-Amino-1-propyl-2-pyrrolidinone;
2,5-Diaminotoluene; Ethyl phenyl ether; Phenylcyanate;
1-(2-Cyclopenten-1-yl)acetone; 2-Amino-3-methylpyridinium;
E-pyridine-3-aldoxime; N-Cyclohexylformamide; 2-Methyl-2-hexenoic
acid; 4-Heptanaminium; and pharmaceutically acceptable forms
thereof (e.g., derivatives thereof; pharmaceutically deliverable
forms thereof; etc.); and/or salts (e.g., pharmaceutically
acceptable salts; etc.) thereof. However, compounds for inhibiting
CntA enzymes of microorganisms from Firmicutes (phylum) can be
configured in any suitable manner, and administering such compounds
can be performed in any suitable manner (e.g., for affecting any
suitable targets).
[0049] Compounds for inhibiting (and/or otherwise affecting) CntA
enzymes can include one or more compounds for inhibiting the CntA
enzymes of microorganisms from Proteobacteria (phylum), such as
where the one or more compounds (and/or compounds generally) can
include any one or more compounds included in Table 7 (e.g., where
the compounds can include specificity for CntA enzymes from
microorganisms from Proteobacteria; where the compounds do not bind
or bind with lower affinity to CntA enzymes from microorganisms
from Firmicutes; where each compound can be representative of a
subset of molecules exerting the same binding energy and such as
with similar structure to the compound; where the compounds can
include higher affinity, as indicated by the binding energy values,
than L-carnitine, to the CntA enzymes; etc.).
TABLE-US-00007 TABLE 7 Examples of Compounds (e.g., molecules) that
can Bind CntA Enzymes of Microorganisms from Proteobacteria (e.g.,
Proteobacteria-L1LUC3 CntA Enzyme) Binding Energy IUPAC (to CntA
enzyme, Structure SMILES code nomenclature Proteobacteria)
##STR00097## C(C(.dbd.O)O)[C@]1([C@@H](OL)C(.dbd.O)O)C(.dbd.O)O
3,4-Anhydro-3- carboxy-2-deoxy- L-threo-pentaric acid -4.8 kcal/mol
##STR00098## C(CO)[NH+](CC(.dbd.O)O)CC(.dbd.O)O 2,2'-[(2-
Hydroxyethyl)imino] diacetic acid -4.6 kcal/mol ##STR00099##
C(c1nn[nH]n1)C(.dbd.O)O 1H-Tetrazol-5- ylacetic acid -4.5 kcal/mol
##STR00100## CC(.dbd.O)C(C(.dbd.O)C)C(.dbd.O)C Diacetylacetone -4.4
kcal/mol ##STR00101## C[C@@H](C(.dbd.O)O)OC(.dbd.O)C (2S)-2-
Acetoxypropanoic acid -4.3 kcal/mol
[0050] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CntA enzymes of the microorganisms from
Proteobacteria (phylum), where the compound includes at least one
(e.g., any one or more; etc.) of:
3,4-Anhydro-3-carboxy-2-deoxy-L-threo-pentaric acid;
2,2'-[(2-Hydroxyethyl)imino]diacetic acid; 1H-Tetrazol-5-ylacetic
acid; Diacetylacetone; (2S)-2-Acetoxypropanoic acid; and
pharmaceutically acceptable forms thereof (e.g., derivatives
thereof; pharmaceutically deliverable forms thereof; etc.); and/or
salts (e.g., pharmaceutically acceptable salts; etc.) thereof.
However, compounds for inhibiting CntA enzymes of microorganisms
from Proteobacteria (phylum) can be configured in any suitable
manner, and administering such compounds can be performed in any
suitable manner (e.g., for affecting any suitable targets).
[0051] Compounds for inhibiting (and/or otherwise affecting) CntA
enzymes can include one or more compounds for inhibiting the CntA
enzymes of microorganisms from Firmicutes (phylum) and
Proteobacteria (phylum) (e.g., inhibiting CntA enzymes of first
microorganisms from Firmicutes as well as CntA enzymes of second
microorganisms from Proteobacteria, etc.), such as where the one or
more compounds (and/or compounds generally) can include any one or
more compounds included in Table 8 (e.g., compounds binding CntA
enzymes associated with Firmicutes, and binding CntA enzymes
associated with Proteobacteria; such as where the compounds can
inhibit products of TMA by CntA in a set of microorganisms across
different taxa, such as across Firmicutes and Proteobacteria; where
each compound can be representative of a subset of molecules
exerting the same binding energy and such as with similar structure
to the compound; where the compounds can include higher affinity,
as indicated by the binding energy values, than L-carnitine, to the
CntA enzymes; etc.).
TABLE-US-00008 TABLE 8 Examples of Compounds (e.g., molecules) that
can Bind CntA Enzymes of Microorganisms from Proteobacteria and
Firmicutes Binding Binding Energy Energy (to CntA (to CntA IUPAC
enzyme, enzyme, Structure SMILES code nomenclature Proteobacteria)
Firmicutes) ##STR00102##
c1cc2c(cc1c1ccc3c(c1)C(.dbd.O)OC3.dbd.O)C(.dbd.O)OC2.dbd.O
4,4'-Biphthalic anhydride -8.9 kcal/mol -8.9 kcal/mol ##STR00103##
O.dbd.C(n1nnc2ccccc12)n1nnc2ccccc12 Bis(1H- benzotriazol-1-
yl)methanone -7.9 kcal/mol -7.9 kcal/mol ##STR00104##
c1ccc2c(c1)C(.dbd.O)c1ccc(cc1C2.dbd.O)S(.dbd.O)(.dbd.O)O 2- Anthra-
quinonesulfonic acid -7.8 kcal/mol -7.8 kcal/mol ##STR00105##
c1ccc2c(c1)C(.dbd.O)N(C2.dbd.O)c1cccc(c1)C#N 3-(1,3-Dioxo-1,3-
dihydro-2H- isoindol-2- yl)benzonitrile. -7.7 kcal/mol -7.7
kcal/mol ##STR00106## c1ccc(cc1)c1nc2ccccc2c(.dbd.O)[nH]1 2-
phenylquinazolin- 4-ol -7.6 kcal/mol -7.6 kcal/mol ##STR00107##
c1ccc2c(c1)nc(s2)c1cc(ccc1O)N 4-Amino-2-(1,3- benzothiazol-2-
yl)phenol -7.5 kcal/mol -7.5 kcal/mol ##STR00108##
c1ccc(cc1)c1c2ccccc2c(.dbd.O)[nH]n1 4-Phenyl-1(2H)- phthalazinone
-7.4 kcal/mol -7.4 kcal/mol ##STR00109##
Cc1c(cc(o1)c1ccc2c(c1)OCO2)C(.dbd.O)O 5-(1,3- Benzodioxol-5-yl)-
2-methyl-3-furoic acid -7.3 kcal/mol -7.3 kcal/mol ##STR00110##
c1ccc2cc(ccc2c1)[C@H]1CCC(.dbd.O)O1 (5R)-5-(2- Naphthyl)dihydro-
2(3H)-furanone -7.2 kcal/mol -7.2 kcal/mol ##STR00111##
Cc1cccc(c1)c1nnc(o1)CCC(.dbd.O)O 3-[5-(3- Methylphenyl)-
1,3,4-oxadiazol-2- yl]propanoic acid -7.1 kcal/mol -7.1 kcal/mol
##STR00112## C#Cc1cc2ccccc2c2c1cccc2 9- ETHYNYL- PHENANTHRENE -6.9
kcal/mol -6.9 kcal/mol ##STR00113##
c1cnccc1c1cc2c([nH]1)CCNC2.dbd.O PHA-767491 -6.8 kcal/mol -6.8
kcal/mol ##STR00114## Cc1c(cccc1O)N 3-Amino-2- methylphenol -6.7
kcal/mol -6.7 kcal/mol ##STR00115## Cc1ccc(cc1)c1ccc(o1)C(.dbd.O)O
5-(4- Methylphenyl)-2- furoic acid -6.6 kcal/mol -6.6 kcal/mol
##STR00116## Cc1ccc2c(c1)c1c(cc(s1)C(.dbd.O)O)CO2 8-Methyl-4H-
thieno[3,2- c]chromene-2- carboxylic acid -6.5 kcal/mol -6.5
kcal/mol ##STR00117## c1ccc(cc1)C(.dbd.O)Oc1cccc(c1)O resorcinol
monobenzoate -6.4 kcal/mol -6.4 kcal/mol ##STR00118##
COc1cc(ccc1C.dbd.O)c1ccccc1 3-Methoxy-4- biphenyl- carbaldehyde
-6.3 kcal/mol -6.3 kcal/mol ##STR00119##
Cc1c2ccc(cc2oc(.dbd.O)c1CC(.dbd.O)O)N (7-Amino-4- methyl-2-oxo-2H-
chromen-3- yl)acetic acid -6.2 kcal/mol -6.2 kcal/mol ##STR00120##
c1cc2c(cc1C(.dbd.O)C(.dbd.O)O)CCC2 2,3-Dihydro-1H- inden-5-
yl(oxo)acetic acid -6.1 kcal/mol -6.1 kcal/mol ##STR00121##
c1ccnc(c1)c1cccc(c1)N 3-(2- Pyridyl)aniline -6.0 kcal/mol -6.0
kcal/mol ##STR00122## Cc1nc([nH]n1)c1ccc(cc1)N 4-(3-Methyl-1H-
1,2,4-triazol-5- yl)aniline -5.9 kcal/mol -5.9 kcal/mol
##STR00123## c1cc(ccc1c1ccc(cc1)N)N Benzidine -5.8 kcal/mol -5.8
kcal/mol ##STR00124## COc1cc(ccc1O)C[C@@H](C(.dbd.O)O)[NH3+]
(DL)-3-O- Methyldopa -5.7 kcal/mol -5.7 kcal/mol ##STR00125##
Cc1cc(c(nc1)N)/C.dbd.C/C(.dbd.O)OC Methyl (2E)-3-(2-
amino-5-methyl- 3- pyridinyl)acrylate -5.6 kcal/mol -5.6 kcal/mol
##STR00126## Cc1cc2cc(oc2nc1)CO (5-Methylfuro[2,3- b]pyridin-2-
yl)methanol -5.5 kcal/mol -5.5 kcal/mol ##STR00127##
c1ccc2c(c1)OC[C@H](O2)C[NH3+] (2R)-2,3-Dihydro- 1,4-benzodioxin-2-
ylmethanaminium -5.4 kcal/mol -5.4 kcal/mol ##STR00128##
CCC(.dbd.O)O[C@H](C)c1ccccc1 R-phenylethyl propionate -5.3 kcal/mol
-5.3 kcal/mol ##STR00129## CC(C)OC(.dbd.O)c1ccccc1 i-propyl
benzoate -5.2 kcal/mol -5.2 kcal/mol ##STR00130##
Cc1ccc(cc1)NC(.dbd.O)C 4-Acetotoluide -5.1 kcal/mol -5.1 kcal/mol
##STR00131## Cc1ccc(c(c1)[C@H](C)[NH3+])C (1S)-1-(2,5-
Dimethylphenyl) ethanaminium -5.0 kcal/mol -5.0 kcal/mol
##STR00132## CC1.dbd.CCC.dbd.C[C@H]1C(.dbd.O)O (1R)-2-Methyl- 2,5-
cyclohexadiene-1- carboxylic acid -4.9 kcal/mol -4.9 kcal/mol
##STR00133## COC(Cc1ccccc1)OC (2,2- Dimethoxy- ethyl)benzene -4.8
kcal/mol -4.8 kcal/mol
[0052] In an example, administering to the patient with the one or
more conditions can include administering, to the patient with the
one or more conditions, a therapeutically effective amount of a
compound for inhibiting the CntA enzymes of the microorganisms from
Firmicutes (phylum) and Proteobacteria (phylum), where the compound
includes at least one (e.g., any one or more; etc.) of:
4,4'-Biphthalic anhydride; Bis(1H-benzotriazol-1-yl)methanone;
2-Anthraquinonesulfonic acid;
3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile.;
2-phenylquinazolin-4-ol; 4-Amino-2-(1,3-benzothiazol-2-yl)phenol;
4-Phenyl-1(2H)-phthalazinone;
5-(1,3-Benzodioxol-5-yl)-2-methyl-3-furoic acid;
(5R)-5-(2-Naphthyl)dihydro-2(3H)-furanone;
3-[5-(3-Methylphenyl)-1,3,4-oxadiazol-2-yl]propanoic acid;
9-ETHYNYLPHENANTHRENE; PHA-767491; 3-Amino-2-methylphenol;
5-(4-Methylphenyl)-2-furoic acid;
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid; resorcinol
monobenzoate; 3-Methoxy-4-biphenylcarbaldehyde;
(7-Amino-4-methyl-2-oxo-2H-chromen-3-yl)acetic acid;
2,3-Dihydro-1H-inden-5-yl(oxo)acetic acid; 3-(2-Pyridyl)aniline;
4-(3-Methyl-1H-1,2,4-triazol-5-yl)aniline; Benzidine;
(DL)-3-O-Methyldopa; Methyl
(2E)-3-(2-amino-5-methyl-3-pyridinyl)acrylate;
(5-Methylfuro[2,3-b]pyridin-2-yl)methanol;
(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethanaminium; R-phenylethyl
propionate; i-propyl benzoate; 4-Acetotoluide;
(1S)-1-(2,5-Dimethylphenyl)ethanaminium;
(1R)-2-Methyl-2,5-cyclohexadiene-1-carboxylic acid;
(2,2-Dimethoxyethyl)benzene; and pharmaceutically acceptable forms
thereof (e.g., derivatives thereof; pharmaceutically deliverable
forms thereof; etc.); and/or salts (e.g., pharmaceutically
acceptable salts; etc.) thereof. In an example, compounds including
different binding affinities (and/or other suitable interaction
parameters) to CntA enzymes depending on the association of the
CntA enzyme to a given taxon (e.g., CntA enzymes of microorganisms
from Proteobacteria; CntA enzymes of microorganisms from
Firmicutes; etc.), and/or compounds with different affinities
generally, can enable different applications, such as where a
compound with high affinity can exert an irreversible inhibition on
the CntA enzyme. However, compounds for inhibiting CntA enzymes of
microorganisms from Firmicutes (phylum) and Proteobacteria (phylum)
can be configured in any suitable manner, and administering such
compounds can be performed in any suitable manner (e.g., for
affecting any suitable targets).
[0053] However, compounds can be configured in any suitable manner,
and administering one or more compounds Silo can be performed in
any suitable manner.
2.2 Determining a Representative Sequence.
[0054] Additionally or alternatively, embodiments of the method 100
can include determining one or more representative sequences of one
or more targets (e.g., CutC enzymes; CntA enzymes; other enzymes;
proteins; other biological targets; non-biological targets; enzymes
associated with at least one of TMA, TMAO, and/or derivatives
thereof; etc.) S120, which can function to determine representative
characteristics of targets for use in modeling and/or experiments
for facilitating compound determination.
[0055] Representative sequences and/or characteristics can include
any one or more of nucleic acid sequence and/or composition; amino
acid sequence and/or composition; functional characteristics;
structural characteristics (e.g., multi-dimensional structure;
etc.); evolutionary characteristics; and/or other suitable
characteristics.
[0056] Representative sequences and/or characteristics are
preferably determined for one or more targets, but can additionally
or alternatively be determined for one or more of control
molecules, compounds, and/or any other suitable molecules. In an
example representative sequences and/or characteristics can be
determined for one or more enzymes, such as where the enzyme can
include at least one CutC enzyme and CntA enzyme, and where the
representative sequence can be representative of a set of sequences
of the enzyme for at least one taxon including at least one of
Firmicutes (phylum) and Proteobacteria (phylum).
[0057] Representative sequences and/or characteristics are
preferably representative for one or more taxons from a set of
microorganism taxa. For example, a representative sequence can be
representative of a set of sequences of one or more targets (e.g.,
CutC enzyme, CntA enzyme, etc.) for one or more microorganism taxa
(e.g., Firmicutes and/or Proteobacteria and/or other suitable taxa;
etc.). In an example, determining one or more representative
sequences can include: generating a sequence similarity network
with target sequences (e.g., CutC enzyme sequences; CntA enzyme
sequences; etc.) associated with (e.g., belonging to; of
microorganisms belonging to; etc.) each taxon of the set of taxa
(e.g., associated with both Firmicutes and Proteobacteria), such as
in order to identify a representative target sequence for each
taxon (e.g., a first representative CutC enzyme sequence for
Firmicutes and a second representative CutC enzyme sequence for
Proteobacteria; a first representative CntA enzyme sequence for
Firmicutes and a second representative CntA enzyme sequence for
Proteobacteria; etc.).
[0058] However, determining one or more representative sequences
S120 can be performed in any suitable manner.
2.3 Generating a Model.
[0059] Additionally or alternatively, embodiments of the method 100
can include generating one or more models (e.g., protein structure
models; etc.) of the one or more targets based on the one or more
representative sequences of the one or more targets S130, which can
function to model one or more targets for facilitating experiments
useful in compound determinations.
[0060] Models preferably include protein structure models (e.g.,
modeling enzyme targets such as CntA enzymes and/or CutC enzymes;
etc.), but can additionally or alternatively include any suitable
models (e.g., modeling any suitable types of targets; etc.). Models
can include any one or more of computational models, models of any
suitable number of dimensions, non-computational models, physical
models, virtual reality models, augmented reality models, and/or
any suitable types of models. Models can be generating using any
suitable processing operations and/or artificial intelligence
approaches described herein.
[0061] Generating models is preferably based on representative
sequences, such as where characteristics of the representative
sequences can be used as inputs and/or parameters for model
generation. For example, generating models can include generating
protein structure models for both the CutC enzyme from Firmicutes
(e.g., Uniprot ID: CoD5P1) (e.g., based on the representative
sequence for the CutC enzyme from microorganisms from Firmicutes;
etc.) and CutC enzyme from Proteobacteria (e.g., Uniprot ID:
B4EYG1) (e.g., based on the representative sequence for the CutC
enzyme from microorganisms from Proteobacteria; etc.) using a
homology modeling approach (and/or any suitable modeling approach),
which can facilitate determination of 3D models (e.g., for proteins
lacking crystallographic data; etc.). For example, generating
models can include generating protein structure models for both the
CntA enzyme from Firmicutes (e.g., Uniprot ID: J3B3E2) (e.g., based
on the representative sequence for the CntA enzyme from
microorganisms from Firmicutes; etc.) and CntA enzyme from
Proteobacteria (e.g., Uniprot ID: L1LUC3) (e.g., based on the
representative sequence for the CntA enzyme from microorganisms
from Proteobacteria; etc.) using a homology modeling approach
(and/or any suitable modeling approach), which can facilitate
determination of 3D models (e.g., for proteins lacking
crystallographic data; etc.).
[0062] However, generating one or more models S130 can be performed
in any suitable manner.
2.4 Determining an Interaction Parameter Associated with a
Control.
[0063] Additionally or alternatively, embodiments of the method 100
can include determining one or more control binding parameters
(and/or other suitable interaction parameters; etc.) to the one or
more targets based on one or more experiments with the one or more
models and one or more control molecules S140, which can function
to determine characteristics describing interactions between one or
more controls and one or more targets.
[0064] Types of binding parameters (e.g., control binding
parameters; compound binding parameters; etc.) preferably include
types of binding parameters included in Tables 1-8 (e.g., binding
energy values, affinity energy values, etc.), but can additionally
or alternatively include association rate, dissociation rate,
half-life of interaction (e.g., between receptor and peptide),
binding constants, binding specificity, thermodynamics associated
parameters (e.g. enthalpy, entropy, Gibbs free energy), parameters
associated with number and type of binding sites (e.g.,
stoichiometry), parameters associated with undesired binding (e.g.,
self-assembly, interference with other proteins, etc.), and/or any
other suitable binding parameters. include any suitable binding
affinity parameters. Interaction parameters preferably include
binding affinities, but can additionally or alternatively include
any suitable parameters associated with control molecules,
compounds, targets, and/or other suitable molecules, and/or
associated with interactions between any combination of such
molecules.
[0065] Experiments preferably include docking simulations (e.g.,
docking simulations using the one or more models and simulating the
binding of one or more control molecules to the one or more models,
such as to the active sites of one or more of the protein structure
models for CutC enzymes and/or CntA enzymes; etc.), but can
additionally or alternatively include one or more of: other
computational simulations (e.g., in silico, etc.); in vitro
experiments, in vivo experiments, benchtop experiments, use of
computational models, and/or any other suitable other
experiments.
[0066] In an example, docking simulations can be performed to
determine control binding parameters (e.g., binding energy values
for the control molecules; etc.) for choline and DMB in relation to
binding CutC enzymes of microorganisms from different taxa (e.g.,
Firmicutes and/or Proteobacteria; etc.), such as based on
performing docking simulations with generated models of the CutC
enzymes for the different taxa (e.g., a first model of the CutC
enzyme from Firmicutes; a second model of the CutC enzyme from
Proteobacteria; etc.) and simulating control molecule (e.g.,
choline and/or DMB) binding to the generated models. In specific
examples, docking simulations can result in binding energy values
of -3.7 kcal/mol for choline in relation to CutC enzyme from
Firmicutes; -4.8 kcal/mol for DMB in relation to CutC enzyme from
Firmicutes; -4.1 kcal/mol for choline in relation to CutC enzyme
from Proteobacteria; and -5.2 kcal/mol for DMB in relation to CutC
enzyme from Proteobacteria, such as where such binding energy
values can indicate a greater affinity of binding for DMB than for
choline (e.g., in the context of competitive inhibition; etc.)
[0067] In an example, docking simulations can be performed to
determine control binding parameters (e.g., binding energy values
for the control molecules; etc.) for L-carnitine in relation to
binding CntA enzymes of microorganisms from different taxa (e.g.,
Firmicutes and/or Proteobacteria; etc.), such as based on
performing docking simulations with generated models of the CntA
enzymes for the different taxa (e.g., a first model of the CntA
enzyme from Firmicutes; a second model of the CntA enzyme from
Proteobacteria; etc.) and simulating control molecule (e.g.,
L-carnitine; DMB; etc.) binding to the generated models. In
specific examples, docking simulations can result in binding energy
values of -4.5 kcal/mol for L-carnitine in relation to CntA enzyme
from Firmicutes; -4.8 kcal/mol for DMB in relation to CntA enzyme
from Firmicutes; -4.3 kcal/mol for L-carnitine in relation to CntA
enzyme from Proteobacteria; and -5.2 kcal/mol for DMB in relation
to CntA enzyme from Proteobacteria.
[0068] Additionally or alternatively, docking simulations can be
performed with any suitable models in relation to any suitable
control molecules and/or any suitable molecules.
[0069] In examples, determining interaction parameters associated
with controls and/or associated with compounds (e.g., in relation
to S150), and/or any suitable portions of embodiments of the method
100 (e.g., determining representative sequences S110; generating
models S120; etc.) can apply one or more of: extracting features,
performing pattern recognition on data, fusing data from multiple
sources, combination of values (e.g., averaging values, etc.),
compression, conversion (e.g., digital-to-analog conversion,
analog-to-digital conversion), performing statistical estimation on
data (e.g. ordinary least squares regression, non-negative least
squares regression, principal components analysis, ridge
regression, etc.), wave modulation, normalization, updating,
ranking, weighting, validating, filtering (e.g., for baseline
correction, data cropping, etc.), noise reduction, smoothing,
filling (e.g., gap filling), aligning, model fitting, binning,
windowing, clipping, transformations, mathematical operations
(e.g., derivatives, moving averages, summing, subtracting,
multiplying, dividing, etc.), data association, multiplexing,
demultiplexing, interpolating, extrapolating, clustering, image
processing, signal processing, visualizing, and/or any other
suitable processing operations.
[0070] In examples, determining interaction parameters associated
with controls and/or associated with compounds (e.g., in relation
to S150), and/or any suitable portions of embodiments of the method
100 (e.g., determining representative sequences S110; generating
models S120; etc.) can apply artificial intelligence approaches
(e.g., machine learning approaches, etc.) including any one or more
of: supervised learning (e.g., using logistic regression, using
back propagation neural networks, using random forests, decision
trees, etc.), unsupervised learning (e.g., using an Apriori
algorithm, using K-means clustering), semi-supervised learning, a
deep learning algorithm (e.g., neural networks, a restricted
Boltzmann machine, a deep belief network method, a convolutional
neural network method, a recurrent neural network method, stacked
auto-encoder method, etc.), reinforcement learning (e.g., using a
Q-learning algorithm, using temporal difference learning), a
regression algorithm (e.g., ordinary least squares, logistic
regression, stepwise regression, multivariate adaptive regression
splines, locally estimated scatterplot smoothing, etc.), an
instance-based method (e.g., k-nearest neighbor, learning vector
quantization, self-organizing map, etc.), a regularization method
(e.g., ridge regression, least absolute shrinkage and selection
operator, elastic net, etc.), a decision tree learning method
(e.g., classification and regression tree, iterative dichotomiser
3, C4.5, chi-squared automatic interaction detection, decision
stump, random forest, multivariate adaptive regression splines,
gradient boosting machines, etc.), a Bayesian method (e.g., naive
Bayes, averaged one-dependence estimators, Bayesian belief network,
etc.), a kernel method (e.g., a support vector machine, a radial
basis function, a linear discriminate analysis, etc.), a clustering
method (e.g., k-means clustering, expectation maximization, etc.),
an associated rule learning algorithm (e.g., an Apriori algorithm,
an Eclat algorithm, etc.), an artificial neural network model
(e.g., a Perceptron method, a back-propagation method, a Hopfield
network method, a self-organizing map method, a learning vector
quantization method, etc.), a dimensionality reduction method
(e.g., principal component analysis, partial lest squares
regression, Sammon mapping, multidimensional scaling, projection
pursuit, etc.), an ensemble method (e.g., boosting, bootstrapped
aggregation, AdaBoost, stacked generalization, gradient boosting
machine method, random forest method, etc.), and/or any suitable
artificial intelligence approach.
[0071] Control molecules preferably include one or more of choline,
DMB, and/or L-carnitine, but can additionally or alternatively
include any suitable substrates that bind to any suitable targets
(e.g., substrates binding to CutC enzymes and/or CntA enzymes;
etc.), any suitable molecules associated with any suitable targets
and/or conditions, and/or any suitable molecules.
[0072] However, determining interaction parameters associated with
one or more controls S140 can be performed in any suitable
manner.
2.5 Determining an Interaction Parameter Associated with a
Compound.
[0073] Additionally or alternatively, embodiments of the method 100
can include determining a set of compound binding parameters
(and/or other suitable interaction parameters; etc.) to the one or
more targets based on a set of experiments with the one or more
models and a library of compounds (e.g., with the potential to
affect the one or more targets, such as the potential to inhibit
CutC enzymes and/or CntA enzymes; etc.) S150, which can function to
determine characteristics describing interactions between one or
more compounds (e.g., potential compounds, etc.) and one or more
targets.
[0074] Compound binding parameters are preferably determined for a
library of compounds including any suitable number of compounds.
Determining the library of compounds can be based on any suitable
parameters (e.g., similarity to structures, number of atoms, and/or
other suitable characteristics of control molecules, molecules
naturally associated with one or more targets, and/or other
suitable molecules; databases of molecules; number of compounds;
type of targets; type of conditions; molecules that do not infringe
Lipinski rules of druggability; etc.). In an example, determining a
library of compounds can include selecting only compounds with a
number of atoms similar to (e.g., within a threshold of) a number
of atoms of choline, DMB, and/or L-carnitine (e.g., within a limit
of 28 atoms; etc.). In a specific example, the library of compounds
can include around 24,000 molecules, but can include any suitable
number of molecules.
[0075] Determining compound binding parameters and/or other
interaction parameters is preferably based on a set of experiments
(e.g., types of experiments described in relation to S140), such as
based on docking simulations using the one or more generated models
(e.g., models for CutC and CntA enzymes for Firmicutes and
Proteobacteria) and simulating binding by the compounds in relation
to the models.
[0076] Determining compound binding parameters can be used to
determine the binding parameters included in Tables 1-8.
[0077] Determining compound binding parameters can be performed in
a same, similar, analogous, or different manner than determining
control binding parameters.
[0078] However, determining interaction parameters associated with
one or more compounds S150 can be performed in any suitable
manner.
2.6 Identifying a Compound.
[0079] Additionally or alternatively, embodiments of the method 100
can include identifying at least one compound (e.g., from the
library of compounds; etc.), based on the one or more control
binding parameters and the set of compound binding parameters S160,
which can function to identify at least one compound for treating a
patient with a condition associated with at least one of
trimethylamine (TMA), trimethylamine N-oxide (TMAO), and
derivatives thereof, and/or for treating a patient with any
suitable conditions.
[0080] Identifying compounds is preferably based on a comparison
between one or more control binding parameters and the set of
compound binding parameters (e.g., filtering a library of compounds
for compounds with corresponding compound binding parameters
greater than one or more of the control binding parameters, etc.).
Additionally or alternatively, identifying compounds can be based
on control binding parameters and compound binding parameters in
any suitable manner, and/or can be based on an y suitable
interaction parameters associated with the one or more control
molecules and/or any suitable interaction parameters associated
with the compounds.
[0081] In an example, identifying compounds can include selecting,
from a library of compounds (e.g., selected based on atom number
similarity to choline and/or DMB, within a limit of 28 atoms;
etc.), compounds with equal or greater binding affinity (e.g., as
indicated by binding energy value; etc.) for CutC enzymes than
choline. In an example, compounds (e.g., with equal or greater
binding affinity for CutC enzymes than choline; etc.) can be
filtered (e.g., further filtered; etc.) based on non-infringement
(e.g., non-violation; etc.) of Lipinski rules of druggability, such
as including molecular weight <500 Daltons, number of H-bonds
donor <5, number of H-bonds acceptor <10, number of N and O
atoms <15, range of partition coefficient log P between -2 and
5, number of rotatable bonds <10, number of ring number <10.
In an example, compounds (e.g., equal or greater binding affinity
for CutC enzymes than choline, and/or not violating Lipinski rules
of druggability; etc.) can be filtered (e.g., further filtered;
etc.) out if the molecule includes any atoms different from
C--H--O--N atoms.
[0082] In an example, identifying compounds can include selecting,
from a library of compounds (e.g., selected based on atom number
similarity to choline, DMB, and/or L-carnitine, within a limit of
28 atoms; etc.), compounds with equal or greater binding affinity
(e.g., as indicated by binding energy value; etc.) for CntA enzymes
than L-carnitine. In an example, compounds (e.g., with equal or
greater binding affinity for CntA enzymes than L-carnitine; etc.)
can be filtered (e.g., further filtered; etc.) based on
non-infringement (e.g., non-violation; etc.) of Lipinski rules of
druggability, such as including molecular weight <500 Daltons,
number of H-bonds donor <5, number of H-bonds acceptor <10,
number of N and O atoms <15, range of partition coefficient log
P between -2 and 5, number of rotatable bonds <10, number of
ring number <10. In an example, compounds (e.g., equal or
greater binding affinity for CntA enzymes than L-carnitine, and/or
not violating Lipinski rules of druggability; etc.) can be filtered
(e.g., further filtered; etc.) out if the molecule includes any
atoms different from C--H--O--N atoms.
[0083] In examples, applying such criteria (and/or any suitable
criteria) in determining compounds can result in any suitable
compounds included in Tables 1-8, such as DMB analogues (e.g., with
Tanimoto coefficient >=0.8, and with equal or greater binding
affinity than DMB to CutC enzymes from Firmicutes and
Proteobacteria; as shown in Table 1; etc.), such as L-carnitine
analogues (e.g., with Tanimoto coefficient >=0.7, and with equal
or greater binding affinity than L-carnitine to CntA enzymes from
Firmicutes and Proteobacteria; as shown in Table 5; etc.).
[0084] Identified compounds are preferably usable for treating
patients with one or more conditions associated with the at least
one of TMA, TMAO, and derivatives thereof, and/or for treating
patients with any suitable conditions. For example, identified
compounds can be used in administering a therapeutically effective
amount of the one or more compounds (e.g., in relation to Silo).
Additionally or alternatively, identified compounds can be used for
any suitable purpose.
[0085] However, identifying compounds S160 can be performed in any
suitable manner.
2.7 Validating a Compound.
[0086] Additionally or alternatively, embodiments of the method 100
can include validating one or more compounds S170, which can
function to experimentally validate and/or otherwise test one or
more compounds.
[0087] Any suitable compounds described herein can be validated
(e.g., experimentally tested, etc.). Compounds can preferably be
validated in relation to effect on one or more targets (e.g., CutC
enzymes, CntA enzymes, etc.). For example, compounds can be
validated in relation to ability of the compounds to inhibit
conversion of choline (e.g., in the context of CutC enzymes, etc.)
or L-carnitine (e.g., in the context of CntA enzymes) into
trimethylamine (TMA) by gut microbiota. As such, compounds can be
validated in relation to their ability to treat one or more
conditions associated with at least one of trimethylamine (TMA),
trimethylamine N-oxide (TMAO), and/or derivatives thereof. However,
any suitable molecules described herein can be validated for any
suitable purpose, such as by applying any one or more techniques
described herein.
[0088] In examples, experiments are carried out using cultures of
bacterial strains that produce either CutC/CutD or CntA/CntB
enzymes. As an example, cultures of Acinetobacter baumranii
(Proteobacteria, aerobic, CntA/CntB producer), Proteus minrabilis,
(Proteobacteria, anaerobic, CutC/CutD producer), Sporosarcina
newyorkensis DSM 235.40 (Firmicutes, CntA/CntB producer, aerobic)
and/or Streptococcus dysgaiactae DSM123147 (Firmicutes, CutC/CutD
producer, anaerobic) can be used.
[0089] In an example, an experimental setup includes evaluation of
the gradual consumption of either choline and/or L-carnitine,
and/or the progressive production of TMA. In a specific example, to
quantify the production of (TMA), cultures are set up in triplicate
in cell culture flasks, using medium supplemented with carnitine or
choline (depending on the case) as a sole carbon source; a sample
is taken from each flask at different time points (e.g., t=0, 4, 8,
12, 24 and 48 h; any suitable time points); optical density at 600
nm is obtained for each sample; and TMA, carnitine, and/or choline
are quantified for each sample (e.g., corresponding to the
different time points; etc.). L-carnitine and choline can
quantified in each sample using standard quantification kits (e.g.,
MAK056 and MAK063, Sigma-Aldrich). TMA quantification can be
carried out using cation exchange ion chromatography equipped with
a separation column and a conductivity detector.
[0090] Additionally or alternatively, CutC or CntA. TMA lyase
activity can be quantified in vitro by incubating, for example: a
cell lysate (typically .about.3 mg protein), an isolated enzyme
(typically .about.30 .mu.g protein), cultured live microbe
(OD.sub.600nm.about.1.0), and/or over cecal lysate with a
d9-labeled synthetic substrate (100 .mu.M, choline or L-carnitine,
during 10-16 h). In such cases, TMA lyase activity can be monitored
by quantifying d9-TMA production by LC/MS/MS analysis. Additionally
or alternatively, TMA production can be detected from supernatants
of the culture cells, using cation-exchange ion chromatography.
However, any suitable quantification techniques can be applied,
such as for validating one or more compounds.
[0091] In a specific example, with obtained baselines of the
consumption of L-carnitine and/or choline, and/or the production of
TMA, a dose response curve of the control compound DMB (e.g., after
incubation by 10-16h) can be obtained on each culture to verify
decrease of TMA production; and one or more dose response curves
can be obtained for each compound (e.g., described in Tables 1-8;
described herein; etc.), such as by incubating the compounds (e.g.,
10-16h) into the corresponding intact cell cultures (e.g., where
cell lysates and/or isolated enzymes can additionally or
alternatively be used), using as substrates L-carnitine and/or
choline at different concentrations (e.g., as an example, 20, 40,
60, 80, 100 .mu.M), and then measuring the TMA production at each
point. In specific examples, a typical concentration used for the
compounds to inhibit production of TMA in an intact cell culture is
at the scale of .about.1 mM. In specific examples, compounds
reduced TMA production by .about.50% or more at each tested
point.
[0092] In a specific example, experiments applying techniques
described above can be performed in Escherichia coli lysates
expressing either CtutC/CutD or CntA/CntB enzymes from
Proteobacteria and/or Firmicutes bacteria species mentioned
above.
[0093] In a specific example, TMA lyase (CutC/CntA) inhibitory
ability, or IC50, under the presence of claimed compounds can be
assessed over isolated enzymes lysates (e.g., at the scale of
.about.30 ug), where enzymes can be expressed in a model organism
(e.g., E. coli Top10) and later purified. In a specific example,
one or more dose response curves can be generated by testing
compounds over the isolated enzymes lysates in increasing
concentrations in the range between 1 and 1000 .mu.M. In specific
examples, IC50 values of compounds are in the range of .about.10
.mu.M.
3. Other.
[0094] Any of the variants described herein (e.g., embodiments,
variations, examples, specific examples, figures, etc.) and/or any
portion of the variants described herein can be additionally or
alternatively combined, aggregated, excluded, used, performed
serially, performed in parallel, and/or otherwise applied.
[0095] Portions of embodiments of the method 100 and/or system 200
can be embodied and/or implemented at least in part as a machine
configured to receive a computer-readable medium storing
computer-readable instructions. The instructions can be executed by
computer-executable components that can be integrated with the
system 200. The computer-readable medium can be stored on any
suitable computer-readable media such as RAMs, ROMs, flash memory,
EEPROMs, optical devices (CD or DVD), hard drives, floppy drives,
or any suitable device. The computer-executable component can be a
general or application specific processor, but any suitable
dedicated hardware or hardware/firmware combination device can
alternatively or additionally execute the instructions.
[0096] As a person skilled in the art will recognize from the
previous detailed description and from the figures and claims,
modifications and changes can be made to embodiments of the method
100, system 200, and/or variants without departing from the scope
defined in the claims.
* * * * *