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

Methicillin Resistant (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, and 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 studies. The synthesized compounds showed very good interactions with PBP2A compared with standard drug Vancomycin, among them compound 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 compound stably sustained up to 20,000ps.Communicated by Ramaswamy H. Sarma.