4.7 Article

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

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 40, Issue 22, Pages 12277-12285

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2021.1971558

Keywords

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

Funding

  1. Ministry of Science and Technology of China [2016YFA0501700]
  2. National Natural Science Foundation of China [91753103, 31700646]
  3. Natural Science Foundation of Shanghai [19ZR1473600]

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Targeting the immunological checkpoint PD-1/PD-L1 with antibodies has shown potential in improving cancer treatment, but comes with drawbacks such as high cost and low patient tolerance. The development of small-molecule PD-1/PD-L1 inhibitors is slow due to challenges like poor pharmacodynamic properties. Recent discoveries of compounds binding the PD-L1/PD-L1 dimer interface offer an alternative approach to inhibit PD-1/PD-L1 interaction efficiently.
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 PDL1 inhibitors.

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