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...

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Published inJournal of biomolecular structure & dynamics Vol. 41; no. 9; pp. 3835 - 3846
Main Authors Matos, Isaac de Araujo, Goes Pinto, Ana Carolina, Ferraz, Matheus Vitor Ferreira, Adan, Wenny Camilla Santos, Rodrigues, Ricardo Pereira, dos Santos, Juliane Xavier, Kitagawa, Rodrigo Rezende, Lins, Roberto Dias, Oliveira, Tiago Branquinho, Costa Junior, Nivan Bezerra da
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 13.06.2023
Subjects
antimicrobial
DHFR
Folic Acid Antagonists - pharmacology
inhibitor
Molecular Docking Simulation
Molecular Dynamics Simulation
Quantitative Structure-Activity Relationship
Staphylococcus aureus
DHFR
antimicrobial
inhibitor
staphylococcus aureus
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Summary: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 2 train , CV LOO and R 2 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
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2022.2057361