Guo Yan, Tong Jinchang, Liang Jianhuai, Shi Kaixin, Song Xinyue, Guo Zichao, Liu Boping, Xu Jianguo
College of Food Science, Shanxi Normal University Taiyuan 030031 China
Key Laboratory for Bio-based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University Guangzhou 510630 China
RSC Adv. 2024 Aug 16;14(36):25908-25917. doi: 10.1039/d4ra03877k.
This study investigated the binding mechanisms of the flavonoids apigenin (Api), kaempferol (Kmp), and quercetin (Que) to the PD-L1 dimer using a combination of molecular modeling and experimental techniques. The binding free energy results demonstrated that the flavonoids could tightly bind to the PD-L1 dimer, with the binding abilities following the trend Que > Kmp > Api. Key residues Ile54, Tyr56, Met115, Ala121, and Tyr123 were identified as important for binding. The flavonoids primarily bind to the C-, F-, and G-sheet domains. The spontaneous formation of the complex systems was mainly driven by hydrophobic forces. Dynamic cross-correlation matrix and secondary structure analyses further indicated that the studied flavonoids could stably interact with the binding sites. ELISA results showed that the flavonoids could effectively block PD-1/PD-L1 interactions, although the inhibitory activity of Api was weaker. Therefore, flavonols might be more effective inhibitors compared to flavones. The findings of this study are expected to contribute to the development of novel flavonoids targeting the PD-1/PD-L1 pathway.
本研究结合分子建模和实验技术，研究了黄酮类化合物芹菜素（Api）、山奈酚（Kmp）和槲皮素（Que）与程序性死亡配体1（PD-L1）二聚体的结合机制。结合自由能结果表明，这些黄酮类化合物能够紧密结合到PD-L1二聚体上，结合能力遵循Que>Kmp>Api的趋势。关键残基异亮氨酸54、酪氨酸56、甲硫氨酸115、丙氨酸121和酪氨酸123被确定为结合的重要位点。黄酮类化合物主要结合到C、F和G片层结构域。复合体系的自发形成主要由疏水作用力驱动。动态交叉相关矩阵和二级结构分析进一步表明，所研究的黄酮类化合物能够与结合位点稳定相互作用。酶联免疫吸附测定（ELISA）结果表明，这些黄酮类化合物能够有效阻断程序性死亡受体1（PD-1）/PD-L1相互作用，尽管芹菜素的抑制活性较弱。因此，黄酮醇可能比黄酮更有效地作为抑制剂。本研究结果有望为开发靶向PD-1/PD-L1通路的新型黄酮类化合物做出贡献。
