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

Authors :
Lovika Mittal
Rajiv Tonk
Amit Awasthi
Shailendra Asthana
Source :
Journal of Medicinal Chemistry. 65:5941-5953
Publication Year :
2022
Publisher :
American Chemical Society (ACS), 2022.

Abstract

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.

Details

ISSN :
15204804 and 00222623
Volume :
65
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....d52bbf82498abaf756494c90d3acf04a
Full Text :
https://doi.org/10.1021/acs.jmedchem.2c00176