4.7 Article

Traversing through the Dynamic Protein-Protein InteractionLandscape and Conformational Plasticity of PD-1 for Small-MoleculeDiscovery

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 8, Pages 5941-5953

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00176

Keywords

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Funding

  1. THSTI
  2. DBT
  3. DPSRU
  4. CSIR [09/981(0007)/2019-EMR-I]

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Monoclonal antibodies 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. The understanding of PD-1's sequence-structure-dynamic-function link is crucial for exploring its binding mechanisms and discovering new small-molecule drugs.
Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1interface have shown remarkable success in treating malignancies, but theymay also initiate lethal immune-related adverse events. Small moleculesmay circumvent the mAb limitations; however, none has entered clinicaltrials targeting PD-1. Its complex protein-protein interaction interfacesnecessitate an atomic-level understanding of recognition and bindingmechanisms. Hence, we have aimed to highlight the PD-1's sequence-structure-dynamic-function link with its cognate ligands and diverselyreported inhibitors. We focus primarily on the anti-PD-1 mAbs, theirmode of actions, and interactions with PD-1 epitopes. The comparison ofco-crystals showed that these ligands/inhibitors harness the PD-1'sconformational plasticity and structural determinants differentially. Therelationship between modulator binding patterns and biological activity isdemonstrated using interactionfingerprinting of all reported human PD-1co-crystals. The significant dynamical events and hot-spot residues underpinned from crystallographic wealth and computationalstudies have been highlighted to expedite small-molecule discovery.

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