Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, China.
Int J Mol Sci. 2023 Jan 11;24(2):1413. doi: 10.3390/ijms24021413.
Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein−ligand complexes in solution, in which the 4′-hydroxy-3′-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy.
使用小分子抑制 PD-1/PD-L1 通路是癌症免疫治疗的重要方法。已有研究表明，辣椒素、去甲氧基姜黄素、6-姜酚和姜黄素等天然化合物通过下调 PD-L1 的表达具有抗癌免疫功能。最近有报道称，小分子促进 PD-L1 二聚化是抑制 PD-1/PD-L1 通路的潜在机制。为了阐明这些化合物对 PD-L1 二聚化的分子机制，进行了分子对接和分子动力学模拟。结果表明，这些化合物可以通过直接靶向 PD-L1 二聚化来抑制 PD-1/PD-L1 相互作用。结合自由能计算表明，辣椒素、去甲氧基姜黄素、6-姜酚和姜黄素与 PD-L1 二聚体具有很强的结合能力，它们的亲和力趋势为去甲氧基姜黄素>辣椒素>6-姜酚≈姜黄素。通过残基能量分解、接触数和非键相互作用分析表明，这些化合物与 PD-L1 二聚体的 C 片层、F 片层和 G 片层片段有紧密的相互作用，这些片段也与 PD-1 相互作用。此外，这些化合物与关键残基 Ile54、Tyr56、Met115 和 Ala121 之间的非极性相互作用在稳定溶液中蛋白-配体复合物方面发挥着关键作用，其中去甲氧基姜黄素、辣椒素、6-姜酚和姜黄素的 4′-羟基-3′-甲氧基苯基和羰基对于小分子与 PD-L1 二聚体的复合物形成具有重要意义。进一步通过自由能景观（FEL）和主成分分析（PCA）分析这些复合物的构象变化，表明这些小分子可以使二聚体结构更加稳定。该工作为食物来源的小分子通过直接靶向 PD-L1 二聚化阻断 PD-1/PD-L1 通路提供了机制见解，并为发现癌症免疫治疗中更有效的小分子药物提供了理论指导。
