基于计算机模拟对JAK2抑制剂的定量构效关系、分子设计和分子动力学研究  

Study on the Quantitative Structure-Activity Relationship,Molecular Design and Molecular Dynamics of JAK2 Inhibitors Based on Computer Simulation Technology

作　　者：袁东峰 周颐 吴和珍 周珊珊[2,3] Yuan Dongfeng;Zhou Yi;Wu Hezhen;Zhou Shanshan(College of Pharmacy,Hubei University of Chinese Medicine,Wuhan,430065;College of First Clinicy,Hubei University of Chinese Medicine,Wuhan,430065;Key Laboratory of Chinese Medicine Resource and TCM Chemistry,Hubei University of Chinese Medicine,Wuhan,430065)

机构地区：[1]湖北中医药大学药学院,武汉430065 [2]湖北中医药大学第一临床学院,武汉430065 [3]湖北中医药大学湖北省中药资源与中药化学重点实验室,武汉430065

出　　处：《化学通报》2022年第11期1376-1386,共11页Chemistry

基　　金：湖北中医药大学青苗计划项目(2021ZZX014);湖北省普通本科高校“荆楚卓越人才”协同育人计划项目(中药学)(鄂教高函[2016]35号)资助。

摘　　要：本文选取了52个对Janus激酶2(JAK2)有抑制作用的小分子化合物,分别使用3D-QSAR中的CoMFA和CoMSIA方法构建了两个可靠的、具有预测能力的模型,并利用分子对接分析数据集化合物与JAK2蛋白的相互作用,表明化合物主要通过氢键和范德华作用与JAK2靶蛋白结合。根据3D-QSAR模型的分析结果,设计了40个化合物,利用构建的模型预测其抑制活性;使用软件预测了化合物的药代动力学(ADME)参数,开展分子对接模拟,最终选择化合物D01和D22与JAK2靶蛋白进行了分子动力学模拟研究,结果显示两个复合物结合构象稳定,与分子对接结果趋势一致。本研究的结果可以为JAK2抑制剂的研发提供一些新的思路,为临床开发此类药物提供理论支撑。In this paper, based on the selected 52 kinds of reported small-molecule compounds with inhibitory effects on Janus Kinase 2(JAK2), two reliable and predictive models were constructed using CoMFA and CoMSIA methods in 3 D-QSAR. Molecular docking was used to analyze the interaction of compounds with JAK2 proteins in the dataset, indicating that compounds bind to JAK2 target proteins mainly through hydrogen bonding and van der Waals interactions. According to the analysis results of the 3 D-QSAR model, 40 compounds were designed, and their inhibitory activities were predicted by the constructed model. The ADME values of the compounds were predicted by software, and molecular docking simulations were carried out. Finally, compounds D01 and D22 were selected to conduct molecular dynamics simulation studies with the JAK2 target protein. The results showed that the binding conformation of the two complexes is stable, which is consistent with the trend of molecular docking. The results of this study can provide some new ideas for the research and development of JAK2 inhibitors, and provide theoretical support for the clinical development of drugs.

关 键 词：JAK2抑制剂 3D-QSAR 分子对接 药代动力学 分子动力学 

分 类 号：TQ460.1[化学工程—制药化工] R914[医药卫生—药物化学]