Computational discovery of small drug-like compounds as potential inhibitors of PD-1/PD-L1 interactions

Abstract

The programmed cell death ligand protein 1 (PD-L1) is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the programmed cell death- 1 protein (PD-1). Cancer immunotherapy based on the monoclonal antibodies targeting the PD-1/PD-L1 pathway has demonstrated therapeutic responses without precedent over a wide range of cancers. However, the antibody-based immunotherapies have several limitations such as high production cost or the induction of severe immune-related adverse effects. Small-molecule inhibitors of the PD-1/PD-L1 pathway are a promising alternative or complementary therapeutic to antibodies. Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In the present study a pharmacophore model was generated based on previously developed compounds and their atomistic structures with the PD-L1 dimer. Structure-based affinity-based virtual screening of small-molecule inhibitors of the PD-1/PD-L1 pathway according to the pharmacophore model followed by a screening in terms of drug-likeness resulted in ten hit compounds of high affinity towards the PD-L1 dimer and the satisfaction to all of the drug-likeness rules. Molecular dynamics (MD) simulations showed that nine of ten compounds formed stable complexes with the PD-L1 dimer as evidenced by the analysis of MD trajectories. Molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) calculation revealed very low binding energies (<-46 kcal/mol) for the interactions of these ligands with the PD-L1 dimer, suggesting that identified compounds may serve as good scaffolds for the design of novel agents of antitumor immunotherapy able to target the PD-1/PD-L1 interaction

Communicated by Ramaswamy H. Sarma

Keywords:

• Programmed cell death ligand protein 1
• pharmacophore
• PD-1/PD-L1 pathway
• small molecule inhibitor

Author contributions

V. V conceived of the idea and V. V. and V.U. planned the work for this publication; V. U., A.D., and V. V. carried out the simulations; V. V. and V. U. analyzed the data and wrote the paper. All authors read and approved the final version.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Belarusian State Program for Biotechnology 2019-2020 [Grant 1.45] and 2021-2025 [Grant 1.1].