Drug Design, Development and Therapy (Mar 2017)
In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA)
Abstract
Junie B Billones,1,2 Maria Constancia O Carrillo,1 Voltaire G Organo,1 Jamie Bernadette A Sy,1 Nina Abigail B Clavio,1 Stephani Joy Y Macalino,1 Inno A Emnacen,1 Alexandra P Lee,1 Paul Kenny L Ko,1 Gisela P Concepcion3 1OVPAA-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; 2Institute of Pharmaceutical Sciences, National Institutes of Health, University of the Philippines Manila, Manila, Philippines; 3Marine Science Institute, College of Science, University of the Philippines Diliman, Quezon City, Philippines 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) in Mycobacterium 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, compound 7 ((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 the Mtb H37Ra strain. Keywords: CADDD, ADMET, TOPKAT, BioA inhibitor, structure-based pharmacophore, pharmacophore, molecular docking, resazurin microtiter assay
