Traversing through the Dynamic Protein–Protein Interaction Landscape and Conformational Plasticity of PD-1 for Small-Molecule Discovery

Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1 interface have shown remarkable success in treating malignancies, but they may also initiate lethal immune-related adverse events. Small molecules may circumvent the mAb limitations; however, none has entered clinical trials targeting PD-1. Its complex protein-protein interaction interfaces necessitate an atomic-level understanding of recognition and binding mechanisms. Hence, we have aimed to highlight the PD-1's sequence-structure-dynamic-function link with its cognate ligands and diversely reported inhibitors. We focus primarily on the anti-PD-1 mAbs, their mode of actions, and interactions with PD-1 epitopes. The comparison of co-crystals showed that these ligands/inhibitors harness the PD-1's conformational plasticity and structural determinants differentially. The relationship between modulator binding patterns and biological activity is demonstrated using interaction fingerprinting of all reported human PD-1 co-crystals. The significant dynamical events and hot-spot residues underpinned from crystallographic wealth and computational studies have been highlighted to expedite small-molecule discovery.