In silico exploration of 6-sulfonyl-8-nitrobenzothiazinone derivatives as mycobacterium tuberculosis GyrB inhibitors: Molecular docking, md simulation, DFT, and pharmacokinetic studies

Abstract

The increasing emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has intensified the need to discover new therapeutic agents essential for bacterial enzymes. DNA gyrase subunit B (GyrB), a validated anti-tubercular target, was explored in this study using a computational approach to identify potent inhibitors among 6-sulfonyl-8-nitrobenzothiazinone derivatives. A collection of 44 structurally diverse derivatives underwent molecular docking, revealing compounds 21 and 26 as top candidates with superior binding scores than the standard drugs, Isoniazid and Pyrazinamide. To further verify these results, molecular dynamics simulations were performed over a 100 ns duration, examining metrics like root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration to confirm complex stability. Additionally, calculations of binding free energy through the MM/GBSA method provided strong validation of the initial docking results, with compound 21 demonstrating the most favourable ΔG_bind (-47.86 kcal/mol), followed closely by compound 26 (-44.60 kcal/mol). Pharmacokinetic profiling indicated high intestinal absorption, acceptable bioavailability, and minimal CYP-mediated metabolic liabilities, particularly for compound 26, which also showed a non-mutagenic profile in AMES predictions. Density functional theory (DFT) analysis revealed narrow energy band gaps and high electrophilicity indices, suggesting superior electronic reactivity and interaction potential. These findings highlight compounds 21 and 26 as promising GyrB inhibitors with favourable stability, pharmacokinetics, and drug-like features, warranting further experimental validation as potential anti-TB drug candidates.

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