Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays.

DNA gyrase and aminoacyl-tRNA synthetases are two essential bacterial enzymes involved in DNA replication, transcription and translation. Flavonoids are plant secondary metabolites with variable phenolic structures. In this study, eight flavonoids structurally similar to quercetin were selected and their ADMET properties were evaluated. Molecular docking and free energy calculations were carried out to examine the binding of these flavonoids to the ATP-binding site and editing domain of DNA gyrase and Isoleucyl-tRNA synthetase, respectively. Taxifolin was found out to be the top lead molecule in both the docking studies with a good number of interactions with the active site amino acids. Further, binding of taxifolin to the proteins was extensively studied using 50 ns molecular dynamics simulation. In vitro anti-tuberculosis activity of taxifolin was evaluated and compared with the standard drugs. Minimal inhibition concentration of taxifolin was found to be ≤ 12.5 μg/ml.