The Polymer Society of Korea

Abstract

PD-L1 is a key immune checkpoint target in cancer immunotherapy, and peptide-based inhibitors are considered promising alternatives to antibodies and small molecules. In this study, six PD-L1-targeting peptides with different lengths and sequences were analyzed using CABS-dock with fully flexible, blind docking. The top 1,000 models for each peptide were aligned to PD-L1 and clustered using ligand RMSD-based K-medoids analysis, followed by contact frequency mapping. The results revealed peptide-dependent differences in binding sites: while some peptides preferentially occupied the PD-1 interaction interface, others bound peripheral or alternative surface regions of PD-L1. These results suggest that high binding affinity to PD-L1 alone does not necessarily guarantee effective blockade of PD-1/PD-L1 interactions, indicating the importance of binding mode-based evaluation in peptide inhibitor screening. Funding: NRF grant funded by the Korea government (MSIT) (RS-2025-02217286).