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

Wei Xia, Liping He, Jingxiao Bao, Yifei Qi, John Z.H. Zhang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)12277-12285
Number of pages9
JournalJournal of Biomolecular Structure and Dynamics
Issue number22
StatePublished - 2022


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

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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