Identification of potential Staphylococcus aureus dihydrofolate reductase inhibitors using QSAR, molecular docking, dynamics simulations and free energy calculation

Herein we describe the use of molecular docking simulations, quantitative structure-activity relationships studies and ADMETox predictions to analyse the molecular recognition of a series of 7-aryl-2,4-diaminoquinazoline derivatives on the inhibition of Staphylococcus aureus dihydrofolate reductase and conducted a virtual screening to discover new potential inhibitors. A quantitative structure-activity relationship model was developed using 40 compounds and two selected descriptors. These descriptors indicated the importance of pKa and molar refractivity for the inhibitory activity against SaDHFR. The values of R-train(2), CVLOO and R-test(2) generated by the model were 0.808, 0.766, and 0.785, respectively. The integration between QSAR, molecular docking, ADMETox analysis and molecular dynamics simulations with binding free energies calculation, yielded the compounds PC-124127620, PC-124127795 and PC-124127805 as promising candidates to SaDHFR inhibitors. These compounds presented high potency, good pharmacokinetics and toxicological profile. Thus, these molecules are good potential antimicrobial agent to treatment of infect disease caused by S. aureus. Communicated by Ramaswamy H. Sarma

Automated summary

In this study, molecular docking simulations, quantitative structure-activity relationships studies, and ADMETox predictions were used to analyze the molecular recognition and inhibition of Staphylococcus aureus dihydrofolate reductase by a series of 7-aryl-2,4-diaminoquinazoline derivatives. A quantitative structure-activity relationship model was developed, demonstrating the importance of pKa and molar refractivity for inhibitory activity. Virtual screening identified PC-124127620, PC-124127795, and PC-124127805 as promising candidates for SaDHFR inhibitors, with high potency and favorable pharmacokinetics and toxicological profiles. These findings suggest these compounds could be potential antimicrobial agents for treating S. aureus infections.