3D-QSAR-Assisted Drug Design: Identification of a Potent Quinazoline-Based Aurora Kinase Inhibitor
3D-QSAR-Assisted Drug Design: Identification of a Potent Quinazoline-Based Aurora Kinase Inhibitor
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DOI：
10.1002/cmdc.201200464
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Hsieh, Hsing-Pang
中科院分区：
文献类型：
--
作者：
Ke, Yi-Yu;Shiao, Hui-Yi;Hsieh, Hsing-Pang
我们描述了3D-QSAR辅助设计的极光激酶A抑制剂，具有改善的理化性质，体外活性和体内药代动力学特征的初始铅。三种不同的3D-QSAR模型的建立和验证，通过使用一组66吡唑（模型I）和呋喃嘧啶（模型II）的化合物与极光激酶A的IC 50值范围从33 nm到10.5 μ m。最好的3D-QSAR模型，模型III，从两个系列的24个训练集化合物构建，显示鲁棒性（r（CV）（2）= 0.54和0.52 CoMFA和CoMSIA，分别）和上级的预测能力为42个测试集化合物（R-pred（2）= 0.52和0.67，CoMFA和CoMSIA）。叠加的CoMFA和CoMSIA模型III的晶体结构的极光激酶A表明，通过减少与Val 147和Leu 139的空间冲突，并通过增加疏水接触Leu 139和Gly 216残基的溶剂暴露区域的酶，以提高活性的配体。基于这些建议，合理重新设计呋喃并嘧啶24（clog P = 7.41; Aurora A IC 50 = 43 nm; HCT-116 IC 50 = 400 nm），鉴别出喹唑啉67（clog P = 5.28; Aurora A IC 50 = 25 nm; HCT-116 IC 50 = 23 nm）。大鼠体内药代动力学研究表明，67在静脉给药后的全身暴露比24更好，并具有进一步开发的潜力。
We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furano-pyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nm to 10.5 mu m. The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r(CV)(2) = 0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R-pred(2) = 0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P = 7.41; Aurora A IC50 = 43 nm; HCT-116 IC50 = 400 nm) led to the identification of quinazoline 67 (clog P = 5.28; Aurora A IC50 = 25 nm; HCT-116 IC50 = 23 nm). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.