Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Lately, small-molecule compounds happen to be reported to bar the PD-1/PD-L1 interaction by creating the dimerization of PD-L1. Each one of these inhibitors were built with a common scaffold and interacted using the cavity created by two PD-L1 monomers. This special interactive mode provided clues for that structure-based drug design, however, also demonstrated limitations for that discovery of small-molecule inhibitors with new scaffolds. Within this study, we revealed the dwelling-activity relationship of the present small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. Throughout the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to possess a more stable binding mode with one PD-L1 monomer compared to other and also the small-molecule inducing PD-L1 dimerization was further stabilized through the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on monomers and also the water bridges involved with ALys124. The unbinding process conjecture demonstrated the PD-L1 dimerization stored stable upon the dissociation of ligands. It’s established that the development and stability from the small-molecule inducing PD-L1 dimerization was the important thing factor for that inhibitory activities of those ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further recommended that every attachment point around the core scaffold of ligands were built with a specific preference for pharmacophore elements when increasing the inhibitory activities by structural modifications. Taken together, the outcomes within this study could advice the structural optimization and also the further discovery of novel small-molecule inhibitors targeting PD-L1

PD-L1 R-group QSAR metadynamics simulation molecular dynamics simulation small-molecule inhibitors.