De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction
De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction
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DOI：
10.1007/s11030-012-9405-y
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发表时间：
2012-10
影响因子：
3.8
通讯作者：
Yanmin Zhang;Haichun Liu;Yu Jiao;H. Yuan;Fengxiao Wang;Shuai Lu;Sihui Yao;Zhipeng Ke;Wenting Tai;Yulei Jiang;Yadong Chen;T. Lu
中科院分区：
文献类型：
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作者：
Yanmin Zhang;Haichun Liu;Yu Jiao;H. Yuan;Fengxiao Wang;Shuai Lu;Sihui Yao;Zhipeng Ke;Wenting Tai;Yulei Jiang;Yadong Chen;T. Lu
血管内皮生长因子（VEGF）及其受体酪氨酸激酶VEGFR-2或激酶插入结构域受体（KDR）已被确定为新的抗癌药物的有前途的目标。为了获得新的有效的KDR抑制剂，我们进行了分子片段置换（MFR）研究，以理解芳基酞嗪和2-（（1H-唑-1-基）甲基）-N-芳基苯甲酰胺基KDR抑制剂的3D-QSAR建模和对接研究。建立了两个较好的3D-QSAR模型（CoMFA与q2，0.671;r2，0.969; CoMSIA与q2，0.608;r2，0.936），用于预测新化合物的生物活性。使用Glide（对接）虚拟筛选由MFR生成的新分子数据库，并使用CoMFA预测、蛋白质-配体相互作用指纹（PLIF）和ADMET分析进一步评估。最终得到了44 N-（吡啶-4-基甲基）苯胺类化合物作为新型KDR抑制剂。本文所建立的工作流程可应用于KDR抑制剂的从头设计和虚拟筛选，并利用成功化合物进一步优化和设计新的KDR抑制剂。
Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA withq2, 0.671;r2, 0.969; CoMSIA withq2, 0.608;r2, 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein–ligand interaction fingerprint (PLIF) and ADMET analysis. 44N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.