In silico Evaluation of Vernonia amygdalina-derived Phytochemicals targeting Dual Sites of Penicillin-binding protein 2a
Abstract
Abstract Context Penicillin-binding protein 2a (PBP2a) drives methicillin resistance in Staphylococcus aureus and is a well-established antistaphylococcal drug target. The enzyme has two binding regions: a transpeptidase active site, and an allosteric site roughly 60 Å away that ceftaroline occupies to trigger the conformational change needed for active-site engagement. Six phytochemicals from Vernonia amygdalina (vernolide, vernodalin, hydroxy-vernolide, luteolin, quercetin, apigenin) were assessed for pharmacokinetic suitability and predicted binding at both sites, relative to ceftaroline. All six satisfied Lipinski's rule of five with high predicted gastrointestinal absorption, though luteolin, quercetin, and apigenin came up as likely cytochrome P450 inhibitors. At the allosteric site, quercetin (− 8.9 kcal/mol) and luteolin (− 8.8 kcal/mol) outscored ceftaroline (− 8.2 kcal/mol), and apigenin matched it; at the active site, only quercetin matched ceftaroline (− 6.5 kcal/mol). Re-docking each site's native ligand against its crystal pose gave root-mean-square deviations (RMSD) of 1.820 Å (allosteric) and 1.491 Å (active), both under the usual 2.0 Å reliability cutoff. Quercetin and luteolin stand out as the strongest leads, with the allosteric site emerging as the more promising, mechanistically relevant site of interaction. Methods Physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties were predicted with SwissADME. Two Protein Data…
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