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

Area of Science:

• Immunology
• Computational Chemistry
• Drug Discovery

Background:

• Antibody therapies targeting the PD-1/PD-L1 immune checkpoint show promise in cancer treatment but face limitations like high cost and poor bioavailability.
• Small-molecule inhibitors offer an alternative but face challenges due to poor pharmacodynamics and the PD-1/PD-L1 binding interface's shallow pocket.
• Inhibiting the PD-L1 dimer interface presents a viable strategy for small molecules to block PD-1/PD-L1 interactions.

Purpose of the Study:

• To quantitatively characterize the binding interactions of small-molecule PD-L1 dimer inhibitors.
• To identify key residues and inhibitor modifications for designing more potent PD-L1 inhibitors.
• To evaluate the effectiveness of the alanine-scanning-interaction-entropy (AS-IE) method for predicting binding free energies.

Main Methods:

• Calculated binding free energies for 35 PD-L1 dimer inhibitors using the alanine-scanning-interaction-entropy (AS-IE) method.
• Identified hotspot residues on PD-L1 crucial for inhibitor binding.
• Pinpointed potential modification sites on the small-molecule inhibitors.

Main Results:

• The AS-IE method demonstrated superior correlation with experimental data compared to the MM/GBSA method.
• Key residues and inhibitor modification groups influencing binding affinity were identified.
• Quantitative insights into PD-L1 dimer-inhibitor interactions were obtained.

Conclusions:

• The AS-IE method is a reliable tool for characterizing small-molecule inhibitor binding to the PD-L1 dimer.
• The findings provide a foundation for designing novel and more potent small-molecule PD-L1 inhibitors.
• This research advances the development of alternative immunotherapies for cancer treatment.