袁东峰,周颐,吴和珍,周珊珊.化学通报,2022,85(11):1376-1386.
基于计算机模拟技术对JAK2抑制剂的定量构效关系、分子设计和分子动力学研究
Quantitative structure-activity relationship, molecular design and molecular dynamics studies of JAK2 inhibitors based on computer simulation technology
投稿时间:2022-01-18  修订日期:2022-04-11
DOI:
中文关键词:  JAK2抑制剂  3D-QSAR  分子对接  药代动力学  分子动力学
英文关键词:Study on the Quantitative Structure-Activity Relationship, Molecular Design and Molecular Dynamics of JAK2 Inhibitors Based on Computer Simulation Technology
基金项目:湖北中医药大学青苗计划项目(2021ZZX014)和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
作者单位E-mail
袁东峰 湖北中医药大学 1781034738@qq.com 
周颐 湖北中医药大学  
吴和珍 湖北中医药大学  
周珊珊 湖北中医药大学第一临床学院 zhouss2009@126.com 
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中文摘要:
      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。
英文摘要:
      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 3D-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 3D-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.
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