Structure‐Guided Identification of Phytochemical Inhibitors Targeting Programmed Death Ligand‐1 Protein for Cancer Immunotherapy

ABSTRACT Tumor cells often evade immune surveillance by overexpressing programmed death ligand‐1 (PD‐L1), which interacts with the programmed death 1 (PD‐1) receptor on T‐cells and suppresses antitumor immune response. Targeting the PD‐1/PD‐L1 immune checkpoint has therefore emerged as a highly effective strategy in modern cancer therapy. While monoclonal antibodies (mAbs) based checkpoint inhibitors have demonstrated remarkable clinical success, their application is constrained by limitations inherent to antibody therapeutics, prompting interest in alternative small‐molecule inhibitors. In this context, naturally derived compounds offer an attractive and potentially safer therapeutic avenue. In the present study, an integrated in silico workflow comprising virtual screening, molecular docking, and molecular dynamics (MD) simulations was employed to identify small‐molecule inhibitors targeting PD‐L1. A curated library of natural compounds was screened using a Python script, to prioritize molecules with high binding affinity toward the PD‐L1 hotspot region. Computational analyses predicted hydnocarpin and calomelanol G as promising candidates capable of engaging PD‐L1 and potentially disrupting its interaction with PD‐1. MD simulations further demonstrated the stability of these PD‐L1/inhibitor complexes over time, supporting their viability as lead compounds. Overall, this computational investigation lays a foundation for subsequent experimental validation and future development of novel small‐molecule immunotherapeutic agents targeting PD‐L1.