Identification of novel antitubercular compounds through hybrid virtual screening approach.
Growing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools. Initially compounds with more than 0.500 Tanimoto similarity coefficient index using functional class fingerprints (FCFP_4) to the reference chemotype were mined from the chemdiv database. Further, the molecular docking was performed to select the compounds on the basis of their binding energies, binding modes, and tendencies to form reasonable interactions with InhA (PDB ID=2NSD) protein. Eighty compounds were evaluated for antitubercular activity against H37RV M. tuberculosis strain, out of which one compound showed MIC of 5.70 microM and another showed MIC of 13.85 microM. We believe that these two new scaffolds might be the good starting point from hit to lead optimization for new antitubercular agents.
Muddassar
Muhammad
M
Center for Chemoinformatics Research, Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Jang
Jae Wan
JW
Hong
Seung Kon
SK
Gon
Hong Seung
HS
Cho
Yong Seo
YS
Kim
Eunice Eunkyung
EE
Keum
Kyo Chang
KC
Oh
Taegwon
T
Cho
Sang-Nae
SN
Pae
Ae Nim
AN
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D016208:Databases, Factual; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000737:chemistry / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D017434:Protein Structure, Tertiary
D000995:Antitubercular Agents; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)