3D-QSAR, molecular docking studies, and binding mode prediction of thiolactomycin analogs as mtFabH inhibitors

Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (mtFabH) has been identified as a novel target for treating tuberculosis. The aim of this study was to understand the binding affinities of thiolactomycin (TLM) analogs for mtFabH based on 3D quantitative structure-activity relationship (3D-QSAR) analysis and molecular docking studies. The 3D-QSAR models produced statistically significant results (comparative molecular field analysis (CoMFA) r2 cv = 0.701, r<SU2</SU = 0.988; comparative molecular similarity indices analysis (CoMSIA) r2 cv = 0.625, r<SU2</SU = 0.969) with 40 TLM analogs. In particular, compounds possessing hydrogen bond acceptors attached to the end of side chains at the C5 position of TLM analogs may enhance their activity. The results of 3D-QSAR models were further compared with structure-based analysis using docking studies with the crystal structure of mtFabH. A plausible binding mode between TLM analogs and mtFabH is proposed.</.