Chemoinformatics-based discovery of new indole-1,2,4 triazole analogues with potential for the treatment of typhoid fever

Abstract

Typhoid fever continues to pose significant public health burden due to the declining efficacy of the current medications, prompting the demand for more effective and newer antibiotics. Herein, in silico drug design techniques including, genetic function approximation based QSAR modeling, molecular docking simulation using PyRx 8.0, druglikeness evaluation using Lipinski’s and Veber’s rules, and pharmacokinetic/toxicity profiling were integrated to investigate the observed anti-Salmonella enterica properties of some indole-1,2,4 triazole conjugates. An optimum tri-parametric QSAR model (R2train = 0.806; R2adj = 0.747; Q2CV = 0.675; R2test = 0.647) hints the predominant influence of molecular surface area on the observed antibacterial properties of the bioactive ligands. Ligand based optimization of ligand 9, the template molecule (Tm) yielded more potent analogues; D1, D2, D3, D4, D5, and D6. The designed ligands were found to bind more strongly to DNA gyrase of the bacteria with ∆G values that range from − 10.0 to -11.5 kcal/mol when compared with Tm and a control drug, Ciprofloxacin (Cipro) which bind to the receptor with ∆G value of -9.6 and − 7.6 kcal/mol, respectively. The high efficacies of the designed ligands are also supported by DFT-based quantum mechanical calculations. In addition, the new ligands display good pharmacokinetics and toxicity profiles. The outcome of this study positions these newly designed bioactive ligands as potential indole-1,2,4 triazole based antibiotics against typhoid fever and are strongly recommended for further in vitro and in vivo investigations.