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

ABSTRACT

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. Critical 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.

KEYWORDS:

• PD-L1
• PD-1
• drug design
• induced fit docking
• molecular dynamics

Acknowledgements

Viktor A. Urban, Polina S. Nazarenko, Stanislav A. Perepechko, Valery G. Veresov performed the simulations and data analysis. Valery G. Veresov conceived and designed the studies, supervised the findings and wrote the manuscript. All authors read and approved the final draft of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Belarusian State Program for Biotechnology of National Academy of Sciences of Belarus 2021–2025 [Grant 1.01], the Belarussian Foundation for Fundamental Research [Grant B20-120]