二苯乙烯类LSD1抑制剂的分子对接及分子动力学模拟研究  

Molecular docking and molecular dynamics simulation study of stilbenes compounds as LSD1 inhibitors

作　　者：陈依帆 赵俊强[1] 杨敏[1] 贺子豪 高云龙 刘鸿仪 徐永涛 CHEN Yi-fan;ZHAO Jun-qiang;YANG Min;HE Zi-hao;GAO Yun-long;LIU Hong-yi;XU Yong-tao(School of Medical Engineering,Xinxiang Medical University,Xinxiang Key Laboratory of Biomedical Information Research,Henan Engineering Laboratory of Combinatorial Technique for Clinical and Biomedical Big Data,Xinxiang 453003,China)

机构地区：[1]新乡医学院医学工程学院,新乡市生物医学信息研究重点实验室,临床与生物医学大数据融合技术河南省工程实验室,河南新乡453003

出　　处：《分子科学学报》2021年第3期206-213,共8页Journal of Molecular Science

基　　金：国家自然科学基金资助项目(21603180);河南省高等学校青年骨干教师培养计划(2017GGJS219);河南省教育信息技术研究课题(1352018039);河南省教育教学改革重点课题(2019SJLX115)。

摘　　要：本研究基于二苯乙烯的结构活性关系,设计了10个组蛋白赖氨酸特异性去甲基化酶1(LSD1)新型抑制剂.采用分子对接的方法并根据对接打分结果对得分最高的化合物进行分子动力学模拟,研究分析小分子和LSD1的相互作用机制,并对其进行ADME(吸收、分布、代谢和排泄)预测.分子对接和分子动力学结果显示设计的小分子与蛋白结合能力更强更稳定,ADME预测结果显示小分子具有良好的生物利用度和类药性.新设计的10个小分子可以作为LSD1抑制剂先导化合物,为新型LSD1抑制剂的研究设计提供新的方法和思路.Histone Lysine Specific Demethylase 1(LSD1)is a highly conserved flavine adenine dinucleotide(FAD)-dependent demethylase belonging to the mo-noamine oxidase(MAO)family.LSD1 inhibitors can be classified into two categories according to their me-chanism of action:irreversible and reversible types.Irreversible LSD1 inhibitors such as Tranylcypromine(TC-PA),Phenelzine,and Pargyline can covalently bind to FAD to inhibit LSD1.However,these inhibitors are less selective for LSD1 and do not inhibit it well,and the irreversible inhibitor binding to FAD also affects other physiological processes that require FAD participation.Therefore,the research of reversible inhibitors of LSD1 has received extensive attention from researchers.In this study,ten novel compounds targeting LSD1 were designed based on the SAR of stilbenes.Molecular docking method was used to study and analyze the binding mode of compounds and LSD1.To verify the reliability of the docking results,molecular dynamics simulation was performed for the compound with the best docking scoring results.And ADME predictions were performed for the designed compounds.Molecular docking and molecular dynamics results showed that the designed compounds have stronger and more stable binding ability to protein,and ADME prediction results showed that the compounds have good bioavailability and drug like properties.The newly designed ten compounds can be used as lead compounds of LSD1 inhibitor for further research,which may provide valuable guidance for the research and design of new LSD1 inhibitors.

关 键 词：LSD1抑制剂 分子对接 分子动力学 ADME预测 

分 类 号：O641[理学—物理化学]