In Silico Molecular Docking Study of Isoquercetin as a Natural Inhibitor of Penicillin-Binding Protein 2 (PBP2) with Comparative Analysis to Ciprofloxacin

The increasing prevalence of antimicrobial resistance has created an urgent need for the discovery of novel antibacterial agents targeting essential bacterial proteins. In the present study, the antibacterial potential of isoquercetin from the ethyl acetate fraction was evaluated through molecular docking against Penicillin-Binding Protein 2 (PBP2; PDB ID: 6G9S) using the Schrödinger Maestro Glide XP docking platform, with ciprofloxacin used as the standard reference drug. The crystal structure of PBP2 was prepared using the Protein Preparation Wizard, and both ligands were optimized through LigPrep prior to docking. The docking results revealed that isoquercetin exhibited a stronger predicted binding affinity than ciprofloxacin, as indicated by a more negative Glide docking score and broader occupation of the catalytic pocket. Detailed interaction analysis showed that isoquercetin formed multiple hydrogen bonds, π–π stacking, π–cation interactions, and hydrophobic contacts with key active-site residues including Lys365, Tyr367, Gln455, Thr547, Phe551, Val550, and Ala548, resulting in stable ligand–protein complex formation. In comparison, ciprofloxacin displayed conventional hydrogen bonding and Mg²⁺-associated stabilization within the active site. The extensive interaction network of isoquercetin suggests a strong potential to inhibit PBP2-mediated bacterial cell wall biosynthesis, thereby supporting its antibacterial activity at the molecular level. Overall, the present findings indicate that isoquercetin may serve as a promising natural antibacterial lead molecule, and further studies involving molecular dynamics simulation, MM-GBSA analysis, in vitro antibacterial assays, and in vivo validation are warranted to confirm its therapeutic applicability.