Identification of a Small Molecule that Binds to the PD-L1 Dimer Interface

24 February 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


In recent years, antibody drugs targeting PD-1/PD-L1 immune checkpoints have shown immense clinical benefits in cancer treatment. However, these drugs suffer from poor patient tolerance, large and difficult-to-control adverse reactions, insufficient oral bioavailability, and low response rates for most solid tumours, which hinder their further application. Due to the poor pharmacodynamic properties and the shallow interface of the PD-1/PD-L1 binding pocket, progress in developing small molecule PD-1/PD-L1 inhibitors that can overcome the limitations of monoclonal antibodies has been slow. Recently, many compounds have been discovered that bind to the PD-L1/PD-L1 dimer interface, providing a promising avenue for inhibiting the interaction of PD-1/PD-L1 with small molecules. Among them, biphenyl compounds that induce PD-L1 dimerization and block the interaction of PD-1 and PD-L1 have shown strong activity. In this study, we conducted virtual screening against the PD-L1 dimer interface and identified a novel biphenyl small molecule inhibitor, ZQ-4, with a unique structure. Molecular dynamics simulations were used to determine the possible binding conformations of ZQ-4 and PD-L1 dimer, and the Alanine Scanning-Interaction Entropy method was used to compare the binding free energy of ZQ-4 and BMS-200. These results provide a foundation for optimizing the hit compound and exploring novel PD-1/PD-L1 small molecule inhibitors.


virtual screening
small molecule
alanine scanning
binding free energy


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