Unlocking Benzosampangine’s Potential: A Computational Approach to Investigating, Its Role as a PD-L1 Inhibitor in Tumor Immune Evasion via Molecular Docking, Dynamic Simulation, and ADMET Profiling
The interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1 is pivotal in tumor immune evasion, making it a key target for cancer immunotherapy. While monoclonal antibodies targeting this pathway have shown significant efficacy, they are associated with limitations such as high costs, toxicity, and resistance development. As a result, the development of small-molecule inhibitors, particularly those derived from natural sources, is increasingly important.
In this study, benzosampangine is identified as a promising PD-L1 inhibitor with potential applications in cancer immunotherapy. Using the high-resolution crystal structure of human PD-L1 (PDB ID: 5O45), we screened 511 natural compounds and identified benzosampangine as a top candidate with notable inhibitory properties. Molecular docking studies revealed that benzosampangine has a strong binding affinity for PD-L1 (-9.4 kcal/mol), outperforming established AUPM-170 inhibitors such as CA-170 (-6.5 kcal/mol), BMS-202 (-8.6 kcal/mol), and pyrvinium (-8.9 kcal/mol). The compound’s binding efficacy is underscored by its robust interactions with key active-site residues (ILE54, TYR56, GLN66, MET115, ILE116, SER117, ALA121, ASP122), including three unique Pi-sulfur interactions with MET115, absent in control inhibitors.
ADMET profiling further supports benzosampangine’s potential, highlighting favorable properties such as solubility, permeability, metabolic stability, and low toxicity, all in compliance with Lipinski’s rule of five. Molecular dynamics simulations confirmed the stability of the benzosampangine-PD-L1 complex, suggesting sustained inhibition of the PD-1/PD-L1 pathway. Additionally, MMGBSA analysis calculated a binding free energy (ΔGbind) of -39.39 kcal/mol for the benzosampangine-PD-L1 complex, with significant contributions from Coulombic, lipophilic, and Van der Waals interactions, corroborating the docking results.
This study provides an in silico investigation of benzosampangine, demonstrating its superior molecular interactions and pharmacokinetic profile compared to known PD-L1 inhibitors, positioning it as a compelling candidate for further development in cancer immunotherapy.