Identification of Small Molecule Inhibitors Targeting PD-L1 Protein Using Computational Tools and an Experimental Assay

Research into PD-L1 is critical in the development of small-molecule anti-cancer drugs. The current chemical compounds that bind to PD-1/PD-L1 exhibit lower efficacy than clinically relevant monoclonal antibodies, necessitating the need for new inhibitors. The aim of this study was to identify and characterise small-molecule inhibitors of PD-1/PD-L1 interaction. In this study, 1,900 compounds were screened against the PDL-1 target to identify binders using the ICM program. Virtual characterization by SwissADME of chemical scaffolds exhibiting high binding affinity to PD-L1 was performed. This was followed by the evaluation of the compounds for their PD-L1/PD-1 inhibitory activity in an in vitro ELISA assay, compared to the control. Analysis of the inhibition of the PD-L1 and PD-1 interaction revealed significant inhibition of the interaction with four compounds (Compound 3; X86577), (Compound 4; X02079), (Compound 6; X53550), and (Compound 9; X14474) compared to the anti-PD-1 neutralizing antibody. The findings present optimised small-molecule inhibitors targeting the PD-1/PD-L1 pathway, which could serve as effective immune checkpoint inhibitors. This work provides valuable insight into therapeutic solutions in addressing unmet medical needs in the oncology field.