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.