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基于分子对接和表面等离子体共振技术筛选IL-15Rα小分子抑制剂

贺毅, 王海霞, 刘敏, 杨健, 孙作厘^*

首都医科大学附属北京安定医院精神疾病诊断与治疗北京市重点实验室，北京 100088

摘要

本研究旨在基于分子对接和表面等离子体共振(surface plasmon resonance, SPR)技术，挖掘与白细胞介素15受体α (interleukin-15 receptor α, IL-15Rα)特异性结合并影响其活性的中药活性分子。用AutoDock分子对接软件进行3 000多种化合物(来自于48种中药)与IL-15Rα的分子模拟对接，筛选出特异性结合的化合物，用基于SPR技术的Biacore T200生物分子互作分析系统对筛选出的目标化合物的结合特异性进行确认，最后用细胞生物学实验验证目标化合物对IL-15Rα的生物学效应。结果显示，甘西鼠尾新酮A (neoprzewaquinone A, Neo)是3 000多种化合物中与IL-15Rα特异性结合亲和力最高的中药活性分子，解离常数(dissociation constant, KD)值为(0.62 ± 0.20) µmol/L。细胞实验结果显示，Neo能显著抑制IL-15诱导的Mo7e细胞的增殖效应，其半数抑制浓度(IC₅₀)为1.075 µmol/L，约为先锋霉素V (Cefazolin，1L-15特异性拮抗剂) IC50的1/120。以上结果表明，Neo是IL-15Rα的特异性抑制剂，可能是一种新的潜在活性药物，可用于以IL-15Rα为靶点的疾病治疗。

关键词： 分子对接; 表面等离子体共振技术; 白介素15受体α; 甘西鼠尾新酮A

Screening of small molecule inhibitors of IL-15Rα using molecular docking and surface plasmon resonance technology

HE Yi, WANG Hai-Xia, LIU Min, YANG Jian, SUN Zuo-Li^*

Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China

Abstract

The study aims to explore the active molecules of traditional Chinese medicine that specifically bind to interleukin-15 receptor α (IL-15Rα) using molecular docking and surface plasmon resonance (SPR) technology. AutoDock molecular docking software was used to perform simulated docking of more than 3 000 compounds from 48 traditional Chinese medicines at IL-15Rα and screen the specific binding compounds. Then Biocore T200 biomolecular interaction analysis system of SPR was used to confirm the binding specificity of the selected target compounds. Finally, the biological effects of the target compounds on IL-15Rα were verified by cell biological experiments. The results showed that neoprzewaquinone A (Neo) possessed the highest specific binding affinity among the active molecules from traditional Chinese medicine, and the dissociation constant (K_D) value was (0.62 ± 0.20) µmol/L. The results of cell experiment showed that Neo significantly inhibited the proliferation of Mo7e cells induced by IL-15, and the IC50 was 1.075 µmol/L, approximately 1/120 of the IC50 of Cefazolin (IL-15 specific antagonist). These results suggest that Neo is a specific inhibitor of IL-15Rα and may be a potential active drug for the treatment of diseases related to the dysfunction of the IL-15Rα signaling.

Key words: molecular docking; surface plasmon resonance;;

收稿日期：　　录用日期：

通讯作者：孙作厘　　E-mail: zuolisun83@163.com

DOI: 10.13294/j.aps.2023.0064

引用本文：

贺毅, 王海霞, 刘敏, 杨健, 孙作厘. 基于分子对接和表面等离子体共振技术筛选IL-15Rα小分子抑制剂[J]. 生理学报 2023; 75 (5): 623-628.

HE Yi, WANG Hai-Xia, LIU Min, YANG Jian, SUN Zuo-Li. Screening of small molecule inhibitors of IL-15Rα using molecular docking and surface plasmon resonance technology. Acta Physiol Sin 2023; 75 (5): 623-628 (in Chinese with English abstract).