MOLECULAR DOCKING ANALYSIS OF GEDUNIN AS A POTENTIAL INHIBITOR OF PENICILLIN-BINDING PROTEIN 2A (PBP2A) IN Methicillin-resistant Staphylococcus. aureus (MRSA)

Abstract

Antibiotic infections are majorly caused by the development of resistance against methicillin in Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus, or MRSA, shows the presence of Penicillin-Binding Protein 2a or PBP2a. This protein is responsible for the reduced effectiveness of β-lactam antibiotics against S aureus. In this study, we aim to explore the binding ability of Gedunin, a limonoid that is obtained from Azadirachta indica or neem, against PBP2a using molecular docking analysis studies. Docking was performed AutoDock Vina against PBP2a receptor at its active and allosteric sites for Gedunin ligand. Re-docking of the co-crystallised ligand was performed which resulted in a RMSD of 0.537 Å. This confirmed the accuracy of the docking protocol used in the study. Further analysis of Gedunin showed favourable affinity towards the active and the allosteric site of the protein. The predicted binding to the active site (−6.935 kcal/mol) was much more than that of the allosteric site (−6.912 kcal/mol). Further, Gedunin showed the presence of the formation of hydrogen bonds, the hydrophobic interactions, π-stacking bonds, and salt bridges along with key amino acid residues for the binding cavity at both sites. To validate the study, a comparative analysis of Gedunin was performed with oxacillin and ceftaroline to ensure that Gedunin can interact with functional regions of PBP2a. Additionally, ADMET analysis and AMES analysis were done using SwissADME and pkCSM, respectively. The results obtained supported the use of Gedunin as a potential inhibitor of PBP2a. Overall, the results indicate the use of Gedunin in developing agents that target PBP2a and after experimental studies validate these computational findings, it can serve as an important naturally obtained product for targeting methicillin-resistant S aureus.