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

Abstract

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 R²_train, CV_LOO and R²_test 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

Keywords:

• DHFR
• inhibitor
• staphylococcus aureus
• antimicrobial

Acknowledgements

The authors thanks ‘Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)’; National Postdoctoral program (PNPD/CAPES); ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)’ and ‘Prof. Daniel F. Kawano for its assistance with the Derek software data acquisition and valuable discussions of the ADME/Tox predictions during the preparation of the manuscript’. Partial computer time was provided by the Brazilian Supercomputing Center (LNCC).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was financed in part by the ‘Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES)’.