Investigating the interaction mechanism of five flavonoids and PD-L1 based on multi-spectroscopy and molecular dynamics

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yijie Cai , Yijun Tu , Hong Cheng , Jianqing Yu
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Abstract

PD-L1 is an important protein overexpressed in various types of cancer. Flavonoids as common antioxidants have extensive bioactivities. In this study, the interaction mechanism and the structure-activity relationship between the five flavonoids and extracellular domain of PD-L1 (PD-L1-ECD) were investigated using integrated spectroscopy and computational simulation. Fluorescence spectra showed that the quenching mechanisms of the interaction between the five flavonoids and PD-L1-ECD were static quenching. Circular dichroism (CD) spectra showed that the five flavonoids caused conformational changes of PD-L1-ECD. Computational simulation data showed the different binding patterns between five flavonoids and PD-L1-ECD. The binding affinity of the five flavonoids which affected by hydrogenation of C2=C3 bond and the substitution of C3 decreased in the following order: luteolin > kaempferol > spinacetin > axillarin > hesperetin. This study suggested that five flavonoids could bind to the PD-L1-ECD, thereby establishing a foundation for developing these compounds as small-molecule PD-L1 inhibitors. Subsequent structure-activity relationship was studied based on distinct binding modes and binding affinity, and it will contribute to structural modifications to optimize therapeutic potency.

Abstract Image

基于多光谱和分子动力学研究5种黄酮类化合物与PD-L1的相互作用机制。
PD-L1是多种癌症中过表达的重要蛋白。黄酮类化合物是常用的抗氧化剂,具有广泛的生物活性。本研究采用积分光谱和计算模拟的方法研究了5种黄酮类化合物与PD-L1胞外结构域(PD-L1- ecd)的相互作用机制和构效关系。荧光光谱显示,5种黄酮类化合物与PD-L1-ECD相互作用的猝灭机制为静态猝灭。圆二色性(CD)光谱显示,5种黄酮类化合物引起PD-L1-ECD构象的改变。计算模拟数据显示,5种黄酮类化合物与PD-L1-ECD的结合模式不同。受C2=C3键加氢和C3取代影响的5种黄酮类化合物的结合亲和力依次为木犀草素b>山樟酚> spinacetin >腋窝素>橙皮苷。本研究提示5种黄酮类化合物可以结合PD-L1 -ECD,为开发这些化合物作为小分子PD-L1抑制剂奠定了基础。基于不同的结合模式和结合亲和力,研究了后续的构效关系,这将有助于结构修饰以优化治疗效力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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