Background: Thioether pleuromutilin derivatives play a dominant role in the epidemic of bacterial resistance to antibacterial agent, and the novel antibacterial compounds would exhibit fresh mechanism of function.Objective: The aim of this study was to determine the connection between thioether pleuromutilin derivatives and 50S ribosomal protein L3, discovering more potent and selective molecules. Methods: We used the 3D-QSAR and Topomer CoMFA to build molecular modeling, obtaining structure characterization required for activity. Molecular docking was conducted to observe the binding model. Besides, the ADMET descriptors were performed to predict the pharmacokinetic properties of new designed agents. Results: The models we built yield reliable statistical information: the values of correlation coefficients and cross validation coefficient are admirable. The results of molecular docking indicate that the designed compounds could bind with receptor more strongly, and that might form greater numbers of hydrogen-bonding with larger amount of residues. Finally, several newly discovered inhibitors were found to pass the entire ADMET test. Conclusion: The CoMFA/CoMSIA and Topomer CoMFA models suggest the vital factors to confirm bactericidal activity of the pleuromutilin derivatives, providing momentous guidance for designing more robust antibacterial agents. From the results of molecular docking and ADMET prediction, we detect that the introduction of F atom or gem-difluoro groups could obviously enhance inhibitory activity.
Keywords: Antibacterial agents, thioether pleuromutilin derivatives, 3D-QSAR, topomer CoMFA, molecular modeling, drug research.