Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study.

Yan Guo,Jianhuai Liang,Yulong Jin,Boping Liu

doi:10.3390/ijms222010924

Abstract

In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy.

Highlights

Programmed cell death-1 (PD-1) [1,2,3] is an immune checkpoint protein that can be expressed on the surface of activated immune cells
In order to clarify this way Whether the compounds CC and epigallocatechin gallate (EGCG) can directly bind to programmed cell death ligand-1 (PD-L1) in a similar issue, a series of molecular modeling approaches were used in the present work, including as RSV, inhibiting PD-1/PD-L1 interactions, remains to be illuminated
In order to molecular docking, molecular dynamics (MD) simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. Clarify this issue, a series of molecular modeling approaches were used in the present work, including molecular docking, MD simulations and MM-PBSA calculations

Summary

Introduction

Programmed cell death-1 (PD-1) [1,2,3] is an immune checkpoint protein that can be expressed on the surface of activated immune cells. Its corresponding ligand, programmed cell death ligand-1 (PD-L1), is overexpressed in many kinds of cancer. When PD-1 binds to PD-L1, immune cells are inhibited from attacking cancer cells; blocking the interaction between PD-1 and PD-L1 is a promising approach to cancer immunotherapy [4]. The pioneering work in this field has mainly focused on monoclonal antibodies (mAbs). Several mAbs, such as nivolumab, avelumab and atezolizumab, have been proven to interrupt the PD-1/PD-L1 pathway and are at the stage of clinic application or approval [5,6,7,8,9].

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Results

Conclusion