Cheminformatics Identification of Phenolics As Modulators of Penicillin-Binding Protein 2a of : A Structure-Activity-Relationship-Based Study

The acquisition of penicillin-binding protein (PBP) 2a in resistant strains of allows for the continuous production of cell walls even after the inactivation of intrinsic PBPs. Thus, the discovery of novel therapeutics with enhanced modulatory activity on PBP2a is crucial, and plant secondary metabolites, such as phenolics, have found relevance in this regard. In this study, using computational techniques, phenolics were screened against the active site of PBP2a, and the ability of the lead phenolics to modulate PBP2a's active and allosteric sites was studied. The top-five phenolics (leads) identified through structure-activity-based screening, pharmacokinetics and synthetic feasibility evaluations were subjected to molecular dynamics simulations. Except for propan-2-one at the active site, the leads had a higher binding free energy at both the active and allosteric sites of PBP2a than amoxicillin. The leads, while promoting the thermodynamic stability of PBP2a, showed a more promising affinity at the allosteric site than the active site, with silicristin (-25.61 kcal/mol) and epicatechin gallate (-47.65 kcal/mol) having the best affinity at the active and allosteric sites, respectively. Interestingly, the modulation of Tyr446, the active site gatekeeper residue in PBP2a, was noted to correlate with the affinity of the leads at the allosteric site. Overall, these observations point to the leads' ability to inhibit PBP2a, either directly or through allosteric modulation with conventional drugs. Further confirmatory in vitro studies on the leads are underway.