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T-cell activation through the blockade of PD-1/PD-L1 interaction by monoclonal antibodies has demonstrated the clinical benefit for patients with diverse types of metastatic cancers. However, a number of limitations when producing and using antibodies hamper their broader clinical application. This awakened a significant interest in design and discovery of small-molecule inhibitors (SMIs) of PD-1/PD-L1 interaction, and several such inhibitors have been identified. However, up to now, many mechanistic details of their inhibitory action remain not fully understood. In this work, a new protocol of enhanced protein conformational sampling combining RosettaLigand and Schrodinger Induced Fit Docking approaches with Molecular Dynamics simulations, preceded by structural modelling of the full-length PD-L1 – dimer in the heterogeneous environment including the membrane and extracellular solution, are used for the prediction of atomistic structures of the complexes of the PD-L1 dimers with BMS-1016, BMS-2007, BMS-4121, BMS-40210, four SMIs with a high inhibitory activity  in vitro  against PD-1/PD-L1 interaction . C ritical protein–ligand interactions responsible for the stabilisation of the complexes of the PD-L1 dimer with SMIs and high inhibitory activities of these SMIs against the PD-1/PD-L1 interaction are revealed. The roles of the membrane and of interaction of PD-L1 with its cis and trans protein partners are also addressed.

molecular simulation

Using PD-L1 full-length structure, enhanced induced fit docking and molecular dynamics simulations for structural insights into inhibition of PD-1/PD-L1 interaction by small-molecule ligands