Computational identification of novel natural inhibitors against triple mutant DNA gyrase A in fluoroquinolone-resistant Typhimurium.

The rising resistance to fluoroquinolones in Typhimurium poses a significant global health challenge. This computational research addresses the pressing need for new therapeutic drugs by utilizing various computational tools to identify potential natural compounds that can inhibit the triple mutant DNA gyrase subunit A enzyme, which is crucial in fluoroquinolone resistance. Initially, the three-dimensional structure of the wild-type DNA gyrase A protein was modeled using homology modeling, and followed by mutagenesis to create the clinically relevant triple mutant (SER83PHE, ASP87GLY, ALA119SER) DNA gyrase A protein structure. The structural stability and integrity of the modeled protein were ensured through rigorous validation. Subsequently, a high-throughput virtual screening of a curated library of natural compounds was conducted to identify potential inhibitors against wild-type and triple-mutant proteins. The selected potent lead molecules comprehensively evaluated their physicochemical properties, ADME/T properties, and binding affinities via ADME/T assessment and molecular docking studies. The safest and most promising ligands were chosen for dynamics studies to analyze their dynamic behavior and protein stability before and after the binding of ligands. Our results showed that the natural compounds from the ChemDiv database, CID: 0407-0108, N039-0003, 1080-0568, and 0099-0261 have binding energies ranging from -4.32 to -5.69 kcal/mol and exhibit excellent physio-chemical properties, affinities, and are stable in their dynamic environments over 100 ns for both wild-type and triple mutant DNA gyrase A complexes. These compounds provide a promising alternative treatment for fluoroquinolone-resistant Typhimurium infections.