Computational analysis of Phanera sirindhorniae flavonoids as potential inhibitors of Mycobacterium tuberculosis DNA gyrase ATPase.

The rise of drug-resistant Mycobacterium tuberculosis underscores the urgent need for safe and bioavailable compounds that target essential bacterial pathways. ATPase domain of DNA gyrase subunit B (GyrB) is a mechanistically distinct and druggable site involved in DNA supercoiling and energy metabolism. In this study, we employed a structure- and system-guided computational pipeline to identify natural flavonoids with multi-target inhibitory potential against GyrB. Naringenin, taxifolin, and quercetin were selected from an initial flavonoid library based on their predicted ATPase inhibition, anti-tuberculosis (TB) activity, and pharmacokinetic properties. Molecular docking and extended molecular dynamics (MD) simulations (3 × 500 ns) validated stable binding poses, with molecular mechanics generalized born surface area (MM-GBSA) calculations ranking taxifolin as the most energetically favorable (-25.6 kcal/mol), supported by persistent interactions with Asp79, and minimal conformational drift. Multi-omics analysis revealed the downregulation of GyrB, ParE, and AtpD, whereas metabolomic shifts in NAD+/NADH and TCA intermediates confirmed redox and respiratory disruptions. Physiologically based pharmacokinetic simulations showed that naringenin achieved the highest predicted lung exposure (0.546 μM at 300 mg), whereas taxifolin offered the best overall balance between binding affinity, exposure, and safety. Synergy modeling with rifampicin identified taxifolin as the top candidate (ZIP synergy score: +4.3). These findings highlight taxifolin and naringenin as promising ATPase-targeting adjuncts for TB therapy and demonstrate how integrated MD and system pharmacology can guide the rational repurposing of natural products.