Bioinfo Chem

Computational Elucidation of EGCG Interaction with PD-L1: A Natural Strategy for Immune Checkpoint Modulation in Melanoma

Shahadat Hossain^1*, Moin Uddin Patwary², Md Abdus Samad³, Hossen Md. Arafat⁴

Epigallocatechin gallate (EGCG) offers a safe, natural alternative to antibody therapies by directly targeting PD-L1 and modulating immune response pathways.

Abstract

Background: The PD-1/PD-L1 immune checkpoint pathway is a well-known mechanism that cancer cells use to escape immune surveillance. Although monoclonal antibodies like Atezolizumab have been approved to block this pathway, they present challenges such as high cost, injection-based delivery, and immune-related side effects. In this context, Epigallocatechin gallate (EGCG), a natural polyphenol from green tea, is considered a potential alternative due to its anticancer and immunomodulatory properties. This study aims to investigate the binding interaction, structural dynamics, drug-likeness, and immunological impact of EGCG as a natural PD-L1 inhibitor using computational approaches.

Methods: The 3D structure of PD-L1 (PDB ID: 5J89) was retrieved from RCSB and prepared using PyMOL. EGCG was obtained from PubChem and docked using PyRx with AutoDock Vina. Molecular dynamics and structural flexibility were assessed via iMODS. Drug-likeness and ADME properties were predicted using SwissADME, while toxicity profiles were analyzed using ProTox-II. Immune-related GO enrichment analysis was conducted to identify functional pathways. Atezolizumab was used as a reference PD-L1 inhibitor for comparative evaluation.

Results: EGCG showed a strong binding affinity (−8.1 kcal/mol) with PD-L1, forming stable hydrogen bonds with residues GLU58, VAL76, and ARG113. Molecular dynamics analysis indicated ligand-induced flexibility and stabilization. SwissADME predicted good GI absorption, drug-likeness, and moderate lipophilicity, while ProTox-II classified EGCG as non-toxic with low risk of hepatotoxicity and immunotoxicity. GO enrichment revealed involvement in key immune pathways, including T-cell activation, cytokine regulation, and immune response modulation. Overall, EGCG demonstrated strong potential as a safe, natural PD-L1 modulator.

Conclusion: This in silico study supports EGCG as a promising, safe, and naturally derived PD-L1 modulator with potential applications in cancer immunotherapy.

Keywords: Epigallocatechin gallate (EGCG), PD-L1 inhibition, Cancer immunotherapy, Molecular docking, Molecular dynamics simulation

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