Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction

The immune checkpoint proteins are those key to the body's immunity which can either boost the immune system to protect the body from pathogens; or suppress the body's immunity system for the goal of self-tolerance. Cancer cells have evolved some mechanisms to boost the immuno-inhibitory checkpoints to bypass the immune system of the body. The binding of Programmed Cell Death-1 (PD-1) protein with its ligand Programmed Cell Death Ligand-1 (PD-L1) promotes this kind of immune-inhibitory signal. The discovery of immune checkpoint inhibitors was started in the early 21st century; with some success through monoclonal antibodies, peptides, and small molecules. Being the most reliable and safest way to target immune checkpoints, the scientific community is exploring possibilities to develop small molecule inhibitors. Among the different scaffolds of the small molecule, the most exposed and researched core molecule is Biphenyl-based scaffolds. We have described all of the possible biphenyl-based small molecules in this article, as well as their interactions with various amino acids in the binding cavity. The link between the in silico, in vitro, and in vivo activities of the PD-1/PD-L1 inhibitors are well connected. The Tyr56, Met115, Ala121, and Asp122 were detected as the crucial amino acids of the PD-1/PD-L1 inhibition. Additionally, a detailed binding pocket analysis of the PD-L1 receptor was carried out, where it was observed and confirmed that the binding pocket is tunnel-shaped and hydrophobic in nature. Finally, the structure-activity relationship of the biphenyl-based small molecule inhibitors was developed based on their activity and the binding interactions.