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

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