Propitious Indazole Compounds as β‐ketoacyl‐ACP Synthase Inhibitors and Mechanisms Unfolded for TB Cure: Integrated Rational Design and MD Simulations

Abstract

AbstractMycobacterium tuberculosis β‐ketoacyl‐ACP synthase I (KasA) involves in mycolic acid biosynthesis for cell wall maintenance; hence, it is a critical target in TB drug design. Thiolactomycin (TLM) and derivatives are the known standard KasA enzyme activity inhibitors. However, TLM analogues have poor activity against KasA protein. Indazole sulphonamide chemotype (JSF‐3285/JFX) was recently reported as a promising KasA enzyme inhibitor. JSF‐3285 mechanism is unclear; thus, it provides a means for designing KasA inhibitors. This study unfolds six hits as unprecedented KasA inhibitors. The inhibitory mechanisms of the screened compounds were investigated and compared with a standard inhibitor (TLM) using integrated molecular informatics and dynamics. JFX, M1, M2, and M5 molecules showed stronger interactions with KasA, having binding energy (kcal/mol) of −44.05, −41.52, −39.51, and −35.9, respectively, against −11.69 for TLM. Molecules showed good predicted inhibitory constants, drug‐likeness, ADME, and synthetic accessibility. KasA complex C‐α atoms RMSD and RMSF showed stable and erratic fluctuations compared to apo KasA. The findings provide potential antimycobacterial lead‐like molecules for future TB drugs.