In-silico design of some tetrazoloquinoline analogs as potent inhibitors of DNA gyrase of Salmonella typhi: QSAR modeling, molecular docking, MD simulation, and ADMET profiling

Abstract

The rising incidences of multi-drug resistance in Salmonella typhi have made the WHO to enlist the bacteria among the highest priority pathogens group that requires urgent attention. In search of novel drug candidates with strong antagonistic effect on DNA gyrase of this bacteria species, a set of anti- S. typhi tetrazoloquinolines were subjected to QSAR modelling. The validated model (R 2 train = 0.86; R 2 adj. = 0.81; R 2 test = 0.74; Q 2 CV = 0.68) was use to design highly potent tetrazoloquinoline analogues; T-1, T-2, and T-3 with in silico MIC values of 15.812 µg/ml, 18.880 µg/ml, and 20.559 µg/ml, respectively. Molecular docking and MM/GBSA studies revealed that T-1, T-2, and T-3 bind to the active sites of DNA gyrase via hydrophobic, electrostatic, hydrogen bond and van der Waals interactions with ∆G values of -48.3 kcal/mol, -50.56 kcal/mol, and -43.92 kcal/mol, respectively. When compared with Ciprofloxacin, a standard antagonist of DNA gyrase which binds to the receptor with ∆G value of -35.92 kcal/mol, the new ligands appear more potent. Also, the stability of the designed ligands and their complexes with DNA gyrase target was confirmed by DFT (B3LYP/6–31G** basis set) calculations and molecular dynamic simulations. In addition, the novel drug candidates were found to possess excellent pharmacokinetic and toxicity profiles and could serve as excellent substitutes to the existing DNA gyrase inhibiting drugs that are currently facing strong resistance from the pathogenic microbe.