Quinoline Heterocyclic Clubbed Hydrazone Derivatives as Potential Inhibitors of Mutant S. aureus DNA Gyrase A; An In Silico Drug Discovery Approach -Molecular Docking, MD Simulation, DFT Analysis and ADMET Predictions

Staphylococcus aureus infections have become a significant public health issue due to increasing the resistance against known antibiotics, especially by Methicillin-Resistant Staphylococcus aureus (MRSA). Fluoroquinolones are broad- -spectrum class of antibiotics mostly utilized in treating various bacterial infections and those caused by S. aureus. Reported data indicated that mutations of Ser84 to Leu, Ser85 to Pro and Glu88 to Lys in DNA gyrase A enzyme are the major cause of fluoroquinolone resistance against S. aureus. Therefore, the development of a novel targeted molecule with potential activity against mutant S. aureus is essential. The antibacterial activity of quinoline-clubbed hydrazone derivatives against S. aureus is noteworthy. However, the mechanism of action of quinoline hydrazone derivatives has not been reported by inhibiting these common mutations of DNA gyrase A.

In this concern, some quinoline hydrazone derivatives as antibacterial agents reported by several research groups have been further studied as mutated S. aureus DNA gyrase A (Pdb id: 8bp2) inhibitors using in silico techniques viz., molecular docking, MD simulation, DFT analysis, and ADMET predictions.

Among the studied compounds, 42, 43, 48 and 49 were found to be the most active and showed the highest docking score (-7.71 to -9.29 kcalmol^-1) by interaction with mutant (Leu84 and Pro85) S. aureus DNA gyrase A. Further, MD simulation results indicated that these compounds exhibited good stability with the targeted macromolecule under dynamic conditions. The most active compound 49 (ʌE = 0.159 eV) attributed to its lower HOMO-LUMO gap, which was an indicator of a potential inhibitor of fluoroquinolone- resistant S. aureus DNA gyrase A enzyme. ADMET prediction study emphasized that both compounds showed a significant safety profile.

The future perspective emphasized that compounds 42, 43, 48 and 49 could be developed as novel inhibitors against fluoroquinolone-resistant DNA gyrase A enzyme on the completion of drug discovery approaches.