Two- and three-dimensional QSAR studies on hURAT1 inhibitors with flexible linkers: topomer CoMFA and HQSAR
Two- and three-dimensional QSAR studies on hURAT1 inhibitors with flexible linkers: topomer CoMFA and HQSAR
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具有柔性接头的 hURAT1 抑制剂的二维和三维 QSAR 研究：拓扑异构体 CoMFA 和 HQSAR
DOI：
10.1007/s11030-019-09936-5
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发表时间：
2019-03
影响因子：
3.8
通讯作者：
Tian Yuanxin
中科院分区：
文献类型：
--
作者：
Zhao Tingting;Zhao Zean;Lu Fengting;Chang Shan;Zhang Jiajie;Pang Jianxin;Tian Yuanxin
HURAT1(人类尿酸转运蛋白1)是治疗高尿酸血症的成功靶点。最近，对hURAT1抑制剂的修饰工作表明，柔性连接体将有利于生物活性。本研究旨在基于构效关系模型(HQSAR和拓扑体CoMFA)研究连接体的贡献，并给出这类结构的修饰策略。应用包含63种化合物的训练集生成了最有效的HQSAR和Topmer CoMFA模型，交叉验证的q2值为0.869/0.818，非交叉验证的相关系数r2为0.951/0.978。为了保证模型的稳健性，采用了Y随机化检验。基于两个模型的外部测试集(21种化合物)的外部预测相关系数(RPRED2)分别为0.910和0.907。此外，模型还用Golbraikh-Tropasha和Roy方法以及其他统计指标进行了验证。结果表明，两种模型都是可靠的。Topmer CoMFA空间/静电等值线和HQSAR原子贡献图说明了控制其抑制能力的结构特征。这些可靠的结果可能为设计更多潜在的hURAT1抑制剂提供重要的指导。
hURAT1 (human urate transporter 1) is a successful target for hyperuricemia. Recently, the modification work on hURAT1 inhibitors showed that the flexible linkers would benefit biological activity. The study aimed to investigate the contribution of the linkers and give modification strategies on this kind of structures based on QSAR models (HQSAR and topomer CoMFA). The most effective HQSAR and topomer CoMFA models were generated by applying the training set containing 63 compounds, with the cross-validated q2values of 0.869/0.818 and the non-cross-validated correlation coefficients r2of 0.951/0.978, respectively. The Y-randomization test was applied to ensure the robustness of the models. The external predictive correlation coefficient (rpred2) grounded on the external test set (21 compounds) of two models was 0.910 and 0.907, respectively. In addition, the models were validated by Golbraikh-Tropsha and Roy methods, as well as other statistical metrics. The results showed that both models were reliable. Topomer CoMFA steric/electrostatic contours and HQSAR atomic contribution maps illustrated the structural features which governed their inhibitory potency. The dependable results could provide important insights to guide the designing of more potential hURAT1 inhibitors.
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影响因子：
2.3
作者：
Anzai, Naohiko;Jutabha, Promsuk;Endou, Hitoshi
通讯作者：
Endou, Hitoshi
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
2.9
作者：
Huang, Dandan;Liu, Yonglan;Liang, Guizhao
通讯作者：
Liang, Guizhao
影响因子：
5.6
作者：
T. Yong;Yizhen Xie;Shaodan Chen;Diling Chen;Jiyan Su;C. Jiao;Huiping Hu;Chun Xiao
通讯作者：
T. Yong;Yizhen Xie;Shaodan Chen;Diling Chen;Jiyan Su;C. Jiao;Huiping Hu;Chun Xiao
DOI：
10.1021/ci970437z
发表时间：
1998-05-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Flower, DR
通讯作者：
Flower, DR