Insights into small molecule inhibitor bindings to PD-L1 with residue-specific binding free energy calculation

Abstract

Targeting the immunological checkpoint PD-1/PD-L1 with antibodies has shown opportunities to improve cancer treatment in recent years. However, antibody therapy is a double-edged sword with high cost, low patient tolerance, lack of oral bioavailability, and a reaction to most solid tumors that prevents the adoption of antibodies. Advancement of small-molecule PD-1/PD-L1 inhibitors that could overwhelm these drawbacks is sluggish because of the poor pharmacodynamic properties and shallow pocket of the PD-1/PD-L1 binding interface. Recently, a number of compounds have been discovered to bind the PD-L1/PD-L1 dimer interface, providing an excellent alternative to inhibit the interaction between PD-1/PD-L1 and small molecules. Quantitative characterization of PD-L1 interactions with these inhibitors will advance the design of novel and efficient inhibitors in the future. Here, the binding free energies of 35 PD-L1 dimer inhibitors have been calculated using the alanine-scanning-interaction-entropy (AS-IE) method. Hotspot residues on PD-L1 and potential modification groups on the inhibitors were identified. The experimental results for the AS-IE method were better correlated than the classical MM/GBSA method. These results may set the stage for the design the more powerful PD-L1 inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• PD-L1
• small molecule
• binding free energy
• alanine scanning

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Ministry of Science and Technology of China (Grant 2016YFA0501700), the National Natural Science Foundation of China (Grant 91753103, 31700646), and the Natural Science Foundation of Shanghai (Grant 19ZR1473600). The computer time was provided by the ECNU Multifunctional Platform for Innovation (001).