组蛋白赖氨酸特异性去甲基化酶1与其抑制剂相互作用的理论研究

Recently, Lysine Specific Demethylase 1 (LSD1) has been extensively studied due to its important application foreground as anti tumor drug targets. Designing and synthetizing LSD1 inhibitors with highly selective, highly active and low toxic will break fresh ground for cancer disease. Based on the previous work, which developed a new type of LSD1 inhibitors (labeled as 1,2,3-triazole−dithiocarbamate hybrids), it can only experimentally prove that the reversible inhibitors vs. substrate belongs to non competitive inhibition while the reversible inhibitors vs. cofactor FAD belongs to competitive inhibition. However, it is unclear whether it is the isosteric inhibition since there is no report about the X-ray structure of the complexes up to now. Importantly, it is impossible to describe the dynamic process of the dissociation/combination processes of cofactor FAD or reversible inhibitors from/to LSD1 by the present experimental techniques. The open questions promote the proposer to investigate these processes in detail by computational methods. In this work, docking will be used to set up the initial complex models of LSD1 with different types of reversible inhibitors. The classic molecular dynamics and steered molecular dynamics will be employed to mimic the dissociation/combination processes and will reveal the detailed information about the interaction of receptor-donor in these inhibition reactions. Explaining and predicting the relationship between the structures and inhibitive activity will offer valuable theoretical basis to screen and synthetize the new type LSD1 inhibitors with better selective and higher efficiency in clinical medicine.

近年来，组蛋白赖氨酸特异性去甲基化酶1（LSD1）作为应用前景较好的抗肿瘤药物靶点成为研究热点，设计并合成选择性强、高效、低毒的LSD1抑制剂将开辟治疗癌症新途径。本课题组已合成出新型含三氮唑氨基二硫代甲酸脂类LSD1抑制剂，并证明此类可逆性抑制剂与底物呈非竞争性抑制；而与辅酶FAD呈竞争性抑制，但尚不清楚是同位或别位抑制作用，更无法观测辅酶或抑制剂与LSD1解离/结合的动态过程。本项目旨在借助理论方法如采用分子对接建立组蛋白特异性酶与不同类型可逆抑制剂复合物模型，使用经典/拉伸分子动力学模拟方法深入探讨可逆抑制剂与蛋白解离/结合的过程，揭示抑制反应过程中受体-配体相互作用，解释和预测LSD1抑制剂结构与其抑制活性的关系，为筛选和合成选择性更好、效率更高的能用于医疗领域的新型LSD1抑制剂提供有价值的理论参考数据。

项目背景：LSD1 在多种肿瘤中高度表达，对其小分子抑制剂的开发已成为癌症治疗的研究热点。.主要研究内容：本项目利用分子对接、经典动力学模拟、拉伸动力学模拟对含三唑二硫代氨基甲酸酯骨架的一类LSD1抑制剂的结合模式以及解离路径进行了系统研究与分析，最终确定得到三唑二硫代氨基甲酸酯类LSD1抑制剂最有利的结合模式，并且发现Arg316和Ser289两残基在此类抑制剂的活性上起关键作用。为进一步构建了药效团，进行虚拟筛选提供了依据。.重要结果及其科学意义：本项目所得拉力功<W>和ΔGexp之间所呈现的高度相关性结论，为缺少晶体结构的情况下，提供了一种预测结合模式的方式。