Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations
Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations
复制标题
使用 3D-QSAR、分子对接和分子动力学模拟鉴定 2,4-二芳基氨基嘧啶类似物作为 ALK 抑制剂
DOI：
10.1007/s00706-017-1999-4
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发表时间：
2017
影响因子：
1.8
通讯作者：
Wu Fan-Hong
中科院分区：
文献类型：
--
作者：
Li Dan-Dan;Wu Fu-Long;Wang Zhong-Hua;Huang Lei-Lei;Yin Yan;Wu Fan-Hong
间变性淋巴瘤激酶(ALK)是开发小分子抗癌药物的一个特别有前途的靶点。本研究采用比较分子场分析(CoMFA)和比较分子相似指数分析(CoMSIA)方法对60个ALK抑制剂进行了三维定量构效关系模型的建立。基于配基的CoMFA(r20.970，q20.660)和CoMSIA(r20.979，q20.623)模型都显示出良好的预测性。生成的等高线地图显示了互动场可能影响活动的区域。然后进行分子对接，以探索这些抑制剂与ALK-4DCE蛋白之间的相互作用。确定了4DCE结合部位的几个关键残基(His32、Gly31、Gly169、Asp170、Val35、Ala100、Pro160、Lys50和Leu30)。分子动力学模拟进一步验证了模型的可靠性。在这项工作中获得的信息不仅可以更好地了解这些分子与ALK受体之间的相互作用，而且还可以用于设计更有效的ALK抑制剂。
AbstractAnaplastic lymphoma kinase (ALK) is a particularly promising target for the development of small molecule anti-cancer drugs. In the present study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 60 ALK inhibitors to build three-dimensional quantitative structure–activity relationship models. Both the ligand-based resultants of CoMFA (r20.970,q20.660) and CoMSIA (r20.979,q20.623) models exhibited good predictability. The resulting contour maps illustrated the regions where interactive fields may affect the activity. Molecular docking was then performed to explore the interactions between these inhibitors and the ALK-4DCE protein. A few key residues (His32, Gly31, Gly169, Asp170, Val35, Ala100, Pro160, Lys50, and Leu30) at the binding site of 4DCE were identified. Molecular dynamics simulation further verified the reliability. The information acquired in this work not only provides a better appreciation of interactions between these molecules and the ALK receptor but could also be applied to design more effective ALK inhibitors.Graphical abstract