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

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