Exploring natural products library to identify potential inhibitors targeting isoniazid-resistant tuberculosis

Mycobacterium tuberculosis (MTB) causing tuberculosis (TB) infection is a leading source of illness and death in developing nations, and the emergence of drug-resistant TB remains a significant global threat and a challenge in treating the disease. Mutations in the inhA and katG genes are connected to the principal molecular mechanism of isoniazid (INH) resistance, and continuous treatment of INH for more than a decade led to the evolution of INH resistant-TB (inhR-TB). Structure-based drug discovery approaches on traditional natural compounds are the contemporary source to identify significant lead molecules. This work focuses on discovering effective small compounds from natural compound libraries and applying pharmacophore-based virtual screening to filter out the molecules. The best-identified hit complexes were used for molecular dynamics simulations (MDS) to observe their stability and compactness. A three-dimensional e-pharmacophore hypothesis and screening generated 62 hits based on phase fitness scores from the pharmacophore-based virtual screening. Molecular docking experiments in Maestro's GLIDE module indicated that ZINC000002383126 and ASN22022 may be potential inhibitors of inhA and katG (native, inhA mutants S94A, Y158A, Y158F and Y158S and D137S, Y229F, S315T, W321F, and R418L mutants of katG). In addition, MDS analysis indicated that the native and mutant docked complexes of inhA and katG had good stability and remained compact in the binding pocket of the targets. In vitro studies can further validate the compounds that can act as INH competitive inhibitors.Communicated by Ramaswamy H. Sarma.