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Methicillin Resistant  Staphylococcus aureus  (MRSA) is a major cause of severe hospital and infections acquired by the population and related morbidity and mortality. In this unique situation, there is a need of dynamic strong drug candidates to control MRSA diseases. Thus, the present work focuses on the synthesis and characterization of pyrimidinones and pyrimidinthiones coupled pyridine derivatives as anti-MRSA agent. The synthesized compounds were characterized by different spectroscopic techniques and evaluated against MRSA strain. Among them,  4e  and  4 g  possessed better antibacterial activity with MIC values of 10 μg and 8 μg respectively. The key determinant of the wide range beta-lactam resistance in MRSA strains is the Penicillin-Binding Protein 2a (PBP2a) but the gene encodes PBP2a which has a low affinity towards β-lactam antibiotics. Because of this, the present investigation focused on the mechanism of PBP2a protein binding studies by  in-silico  studies. The synthesized compounds showed very good interactions with PBP2A compared with standard drug Vancomycin, among them compound  4 g  showed better interaction with the binding score of −9.8 kcal/mol. Antibacterial activity was validated with molecular docking and molecular dynamic simulation. Simulation results revealed that protein-ligand interactions of  4 g  compound stably sustained up to 20,000ps. Communicated by Ramaswamy H. Sarma

Design, synthesis of pyridine coupled pyrimidinone/pyrimidinthione as anti-MRSA agent: Validation by molecular docking and dynamics simulation