Molecular docking simulation, drug-likeness assessment, and pharmacokinetic study of some cephalosporin analogues against a penicillin-binding protein of Salmonella typhimurium.

In pursuit of novel antibiotics that could curb the growing trend of multidrug resistance by Salmonella typhimurium, a data set of some cephalosporin analogues were subjected to Molecular Docking based virtual screening against a penicillin-binding protein (PBP 1b) of the bacterium to ascertain the binding affinity values of the bioactive ligands against the active sites of the PBP 1b protein target using the AutoDock Vina Software. Three compounds with binding affinity values ranging from -7.8 kcal/mol to -8.2 kcal/mol were selected as the most promising leads. The selected compounds also displayed better potencies against the bacterium when compared with Cefuroxime (binding affinity = -6.4 kcal/mol), a standard ß-lactam antibiotic used herein for quality control and assurance. Furthermore, evaluation of the drug-likeness and ADMET properties of the three most promising leads revealed that they possess good oral bioavailability and excellent pharmacokinetic profiles. It is hoped that the findings of this study will provide an excellent template for developing more potent ß-lactam antibiotics against Salmonella typhimurium.

Molecular docking-based virtual screening, drug-likeness, and pharmacokinetic profiling of some anti-Salmonella typhimurium cephalosporin derivatives.

Objective: The rising cases of resistance to existing antibiotic therapies in Salmonella typhimurium has made it necessary to search for novel drug candidates. The present study employed the molecular docking technique to screen a set of antibacterial cephalosporin analogues against penicillin-binding protein 1a (PBP1a) of the bacterium. This is the first study to screen cephalosporin analogues against PBP1a, a protein central to peptidoglycan synthesis in S. typhimurium. Methods: Some cephalosporin analogues were retrieved from a drug repository. The structures of the molecules were optimized using the semi-empirical method of Spartan 14 software and were subsequently docked against the active sites of PBP1a using AutoDock vina software. The most potent ligands were chosen as the most promising leads and subsequently subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling using the SwissADME online server and DataWarrior chemoinformatics program. The CABSflex 2.0 server was used to carry out molecular dynamics (MD) simulation on the most stable ligand-protein complex. Results: Compounds 3, 23, and 28 with binding affinity (ΔG) values of -9.2, -8.7, and -8.9 kcal/mol, respectively, were selected as the most promising leads. The ligands bound to the active sites of PBP1a via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analyses of the ligands revealed that they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD study revealed that the most active ligand bound favorably and dynamically to the target protein. Conclusion: The findings of this research could provide an excellent platform for the discovery and rational design of novel antibiotics against S. typhimurium. Additional in vitro and in vivo studies should be carried out on the drug candidates to validate the findings of this study.