College of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250200, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Int J Mol Sci. 2024 Oct 19;25(20):11250. doi: 10.3390/ijms252011250.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and it is highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to its lower risk of side effects and personalized medication. Excessive activation of PI3Kδ in DLBCL leads to abnormal activation of the PI3K/Akt pathway, promoting the occurrence and development of DLBCL. The side effects of existing PI3Kδ inhibitors limit their clinical application. The discovery of PI3Kδ inhibitors with novel structures and minimal side effects is urgently needed. This study constructed a PI3Kδ inhibitor screening model to screen natural product libraries. Revealing the mechanism of natural product therapy for DLBCL through network pharmacology, kinase assays, and molecular dynamics. The results of molecular docking indicated that Silibinin had a high docking score and a good binding mode with PI3Kδ. The results of network pharmacology indicated that Silibinin could exert therapeutic effects on DLBCL by inhibiting PI3Kδ activity and affecting the PI3K/Akt pathway. The kinase assays indicated that Silibinin concentration dependently inhibited the activity of PI3Kδ. The results of molecular dynamics indicated that Silibinin could stably bind to PI3Kδ. Silibinin was a structurally novel 3,5,7-trihydroxychroman-4-one PI3Kδ inhibitor, providing valuable information for the subsequent discovery of PI3Kδ inhibitors.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的淋巴瘤，其侵袭性强，异质性高。由于靶向治疗的副作用风险较低且能够实现个体化用药，因此仍然是临床中的主要治疗方法。在 DLBCL 中，PI3Kδ 的过度激活导致 PI3K/Akt 通路异常激活，从而促进 DLBCL 的发生和发展。现有 PI3Kδ 抑制剂的副作用限制了其临床应用。因此，迫切需要发现具有新型结构和最小副作用的 PI3Kδ 抑制剂。本研究构建了 PI3Kδ 抑制剂筛选模型，用于筛选天然产物文库。通过网络药理学、激酶测定和分子动力学揭示天然产物治疗 DLBCL 的机制。分子对接结果表明，水飞蓟素与 PI3Kδ 具有较高的对接评分和良好的结合模式。网络药理学结果表明，水飞蓟素通过抑制 PI3Kδ 活性和影响 PI3K/Akt 通路对 DLBCL 发挥治疗作用。激酶测定结果表明，水飞蓟素能够浓度依赖性地抑制 PI3Kδ 的活性。分子动力学结果表明，水飞蓟素能够稳定地与 PI3Kδ 结合。水飞蓟素是一种结构新颖的 3,5,7-三羟基色原酮-4-酮 PI3Kδ 抑制剂，为后续发现 PI3Kδ 抑制剂提供了有价值的信息。
