In silico identification of potential inhibitors of Mycobacterium tuberculosis DNA gyrase from Phytoconstituents of Indian medicinal plants

DNA gyrase, the sole type-II topoisomerase in Mycobacterium tuberculosis , plays a critical role in the bacteria's survival by catalyzing the DNA topology change and is considered a crucial drug target for tuberculosis treatment. The emergence of drug resistance in Mycobacterium tuberculosis, specifically against the second line of drugs (fluoroquinolones) targeting DNA gyrase, necessitates the identification of novel compounds that can effectively interact with the enzyme. In this study, phytochemicals from the Indian medicinal plant database were systematically screened to identify potential inhibitors effective against both wild-type and mutant forms of DNA gyrase. Through successive stages of virtual screening, ADMET-based hit refinement, and molecular dynamics simulations, compound IM7 was identified as a promising inhibitor. The MMPBSA binding free energy analysis validates the docking results, suggesting IM7 forms a stable complex with the gyrase. The principal component analysis also supported the stability of the complex, and thus, this molecule emerged as a promising drug candidate against Mycobacterium tuberculosis . Overall, this study establishes IM7 as a promising DNA gyrase inhibitor for Mycobacterium tuberculosis therapy, demonstrating a unique dual-binding mechanism of action that effectively targets both the ATP and QRDR sites in native and mutant enzymes. We anticipate wet-lab experiments and clinical studies to support this computational analysis, which may assist in inhibiting Mycobacterium tuberculosis infections. • Investigated the potential inhibitors of native and mutated forms of Mycobacterium tuberculosis DNA gyrase using in silico tools. • Virtual screening and pharmacokinetic property studies identified IM7 from the IMPPAT 2.0 database as a potential inhibitor of native and mutated strains of Mycobacterium tuberculosis DNA gyrase. • Molecular dynamics simulations confirm the stability of IM7 complexes with DNA gyrase, indicating its promise as a new drug candidate that binds to both the ATP and QRDR regions of native and mutant gyrase. • Principal component analysis and MMPBSA binding free energy analysis corroborated the findings, suggesting strong binding interactions between the lead molecule and DNA gyrase.