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In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA)

Authors Billones JB, Carrillo MCO, Organo VG, Sy JBA, Clavio NAB, Macalino SJY, Emnacen IA, Lee AP, Ko PKL, Concepcion GP

Received 16 August 2016

Accepted for publication 6 December 2016

Published 2 March 2017 Volume 2017:11 Pages 563—574


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Georgios D. Panos

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

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