Design of novel anti-MRSA inhibitors: a computational study integrating QSAR, ADMET, and molecular dynamics simulations

Sulfonyl fluoride has attracted much attention due to its activatable reactivity, excellent biocompatibility and reactivity to proteins. In addition, sulfonyl fluoride has stronger spatial sensitivity and temporal sensitivity and can be used to study the localization and function of proteins. In a recent publication, a series of newly designed arylethenesulfonyl fluoride derivatives have emerged as highly effective inhibitors against methicillin-resistant Staphylococcus aureus (MRSA), showing impressive antiviral activity and antibiofilm properties. In order to gain a deeper understanding of the relationship between the structure and activity, this study used computational simulation methods such as 3D-QSAR, molecular docking and dynamics analysis to systematically study the structure-activity relationship of a series of arylethenesulfonyl fluoride compounds. Two different reliable 3D-QSAR statistical models, CoMFA (q2 = 0.668, SEE = 0.164, r2 = 0.962, F = 178.682) and CoMSIA/SEH (q2 = 0.6, SEE = 0.237, r2 = 0.916, F = 130.460), were established using a data set of 82 compounds. Analysis of three-dimensional contour maps revealed key structural features influencing molecular activity. Molecular docking studies examined the interaction modes between small molecules and the target protein SarA, identifying crucial residues such as LYS123. Based on the results and comparison of model prediction, we constructed 8 new molecules with better inhibitory activity than the template compounds. Molecular dynamics simulations verified the stable binding of the new molecules to the protein complex. The binding free energy results calculated by MM/PBSA are consistent with the activity prediction. Pharmacokinetic evaluation showed that the new molecule has good potential for clinical application. The new molecules studied here will provide the necessary theoretical basis for the synthesis and activity evaluation of new MRSA inhibitors. This work reports a comprehensive computational study on a series of sulfonyl fluoride analogs, aiming to design novel anti-MRSA drugs based on the derived models.