Inventi Rapid: Molecular Modeling

Inventi:prmm/115501/26

Structure-Based and Ligand-Based Computer-Aided Drug Designing for Identification of Potential Methicillin-Resistant Staphylococcus aureus Protein 2a Inhibitors

Antimicrobial resistance, particularly methicillin-resistant Staphylococcus aureus (MRSA), creates an urgent need for alternative therapeutic strategies. This study applied an integrated computer-aided drug-designing workflow to identify and prioritize small molecules with potential activity against MRSA-associated protein targets. Three crystallographic structures—PBP2a (PDB 4CJN), mevalonate kinase (PDB 2X7I) and 3-methyladenine DNA glycosylase I (PDB 4AIA)—were evaluated using structural quality assessment, solvent accessibility, binding-site analysis and druggability prediction. The 4CJN PBP2a structure was prioritized because it showed the highest solvent-accessible area and the most favorable druggability assessment among the three evaluated targets. Thirteen known antimicrobial or bioactive molecules were subsequently assessed by molecular docking. Ribavirin showed the most favorable tabulated docking score against 4CJN (-6.1 kcal/mol), followed by penicillin (-5.9 kcal/mol), tigecycline and dalbavancin (-5.8 kcal/mol each) and mupirocin and rifampicin (-5.6 kcal/mol each). Penicillin and ribavirin were selected for molecular-dynamics analysis and 100-ns simulations were performed using GROMACS. In-vitro assessment by Kirby–Bauer disc diffusion against Staphylococcus aureus MTCC-7443 produced zones of inhibition of 21.03 mm for penicillin and 19.34 mm for ribavirin. The findings support the utility of an integrated structure-based, ligand-based, ADME/drug-likeness, docking, molecular-dynamics and experimental-screening workflow for prioritizing candidates for further investigation. The computational findings should be regarded as lead-generation evidence rather than proof of clinical efficacy and the reported in-vitro organism should be distinguished from a confirmed MRSA isolate....