新型α-萘巯基氨基酸乙酯类LSD1抑制剂的构建、活性评价与分子模拟研究

Construction, Activity Evaluation and Molecular Simulation Study of α-Naphthylthiol Amino Acid Esters as Novel LSD1 Inhibitors

关键词:  组蛋白赖氨酸特异性去甲基化酶1(LSD1)  抑制剂  分子对接  动力学模拟

Key words:  novel lysine specific demethylase 1(LSD1)  inhibitors  molecular docking  dynamic simulation

摘要:

目的 设计合成结构新颖的萘巯基氨基酸乙酯类组蛋白赖氨酸特异性去甲基化酶1(lysine specific demethylase 1，LSD1)抑制剂，评价其LSD1抑制活性与选择性，并通过分子对接和动力学模拟探讨结合机制。方法 基于先导化合物3a与LSD1蛋白的结合模式，在化合物结构中固定平面疏水性的萘环，同时引入具有亲水性的氨基片段，采用三组份一锅法构建α-萘巯基氨基酸乙酯小分子化合物。采用课题组自主构建的LSD1筛选平台测试化合物在5.0，1.0 μmol·L^–1浓度下对LSD1的抑制率，测试活性最好的化合物的IC₅₀值及对MAO-A和MAO-B的抑制活性，并通过分子对接和动力学模拟研究其结合机制。结果 共合成13个目标化合物，均对LSD1有很好的抑制作用，其中有9个化合物在1.0 μmol·L^–1浓度下对LSD1抑制率>50.0%，且化合物3l活性最佳，IC₅₀值为0.17 μmol·L^–1，是阳性对照的174倍，对MAO-A和MAO-B有很好的选择性。分子对接和动力学模拟表明化合物3l通过多重作用与LSD1结合来抑制其活性。结论 α-萘巯基氨基酸乙酯类结构可作为先导化合物或活性片段，为基于结构的药物设计进行后续LSD1抑制剂的设计打下良好基础。

Abstract:

OBJECTIVE To design and synthesize novel α-naphthylthiol amino acid ester lysine specific demethylase 1(LSD1) inhibitors, evaluate their inhibitory activity with selectivity against LSD1, and explore their binding mechanism through molecular docking and dynamics simulation. METHODS Based on the binding mode of hit compound 3a with LSD1, the α- naphthyl mercapto amino acid ethyl ester small molecule compound were designed by fixing the planar hydrophobic naphthyl ring in the structure, while introducing hydrophilic amino fragment, and they were prepared through a multi-component one-pot cascade reaction. All the compounds were evaluated for their inhibitory activity against LSD1 at concentrations of 5.0 and 1.0 μmol·L^–1 using the LSD1 screening platform of research group. The most potent compound was tested for its IC₅₀ value and enzyme selectivity over MAO-A and MAO-B, and its binding mode was investigated through molecular docking and dynamics simulation.RESULTS A total of 13 compounds were obtained, all of which exhibited significant inhibitory effects on LSD1. Among them, nine compounds showed an inhibitory rate of over 50.0% against LSD1 at a concentration of 1.0 μmol·L^–1, while compound 3l displaying the best activity with an IC₅₀ value of 0.17 μmol·L^–1, 174 times higher than the positive control. It also showed excellent selectivity towards MAO-A and MAO-B. Molecular docking and dynamics simulations indicated that compound 3l inhibited the activity of LSD1 through multiple interactions. CONCLUSION The structures of α-naphthylthiol amino acid ester can serve as lead compounds or active fragments, laying a solid foundation for the subsequent design of LSD1 inhibitors based on structure-oriented drug design.