title: In silico discovery and in vitro activity of inhibitors againstMycobacterium tuberculosis7,8-diaminopelargonic acid synthase (MtbBioA).
abstract: Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) inMycobacterium tuberculosis(Mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound7((Z)-N-(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 μg/mL concentration against the growth of theMtbH37Ra strain.
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines; Institute of Pharmaceutical Sciences, National Institutes of Health, University of the Philippines Manila, Manila, Philippines.
authors.forename: Junie B
authors.initials: JB
authors.lastname: Billones
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Maria Constancia O
authors.initials: MC
authors.lastname: Carrillo
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Voltaire G
authors.initials: VG
authors.lastname: Organo
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Jamie Bernadette A
authors.initials: JB
authors.lastname: Sy
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Nina Abigail B
authors.initials: NA
authors.lastname: Clavio
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Stephani Joy Y
authors.initials: SJ
authors.lastname: Macalino
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Inno A
authors.initials: IA
authors.lastname: Emnacen
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: Lee
authors.affiliation: OVPAA-EIDR Program, "Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines", Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines.
authors.forename: Paul Kenny L
authors.initials: PK
authors.lastname: Ko
authors.affiliation: Marine Science Institute, College of Science, University of the Philippines Diliman, Quezon City, Philippines.
authors.forename: Gisela P
authors.initials: GP
authors.lastname: Concepcion
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C515407:7,8-diaminoperlargonic acid aminotransferase, Mycobacterium tuberculosis; D000637:Transaminases
keywords: ADMET; BioA inhibitor; CADDD; TOPKAT; molecular docking; pharmacophore; resazurin microtiter assay; structure-based pharmacophore