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[1]徐闻曦,蔡晓然,郑小娇,等.TNNI3K抑制剂3D-QSAR的研究及虚拟筛选[J].武汉工程大学学报,2018,40(05):485-493.[doi:10. 3969/j. issn. 1674-2869. 2018. 05. 003]
　XU Wenxi,CAI Xiaoran,ZHENG Xiaojiao,et al.Virtual Screening and 3D-QSAR Study of TNNI3K Inhibitors[J].Journal of Wuhan Institute of Technology,2018,40(05):485-493.[doi:10. 3969/j. issn. 1674-2869. 2018. 05. 003]
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TNNI3K抑制剂3D-QSAR的研究及虚拟筛选(/HTML)
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《武汉工程大学学报》[ISSN:1674-2869/CN:42-1779/TQ]

卷:
40
期数:
2018年05期
页码:
485-493
栏目:
化学与化学工程
出版日期:
2018-12-27

文章信息/Info

Title:
Virtual Screening and 3D-QSAR Study of TNNI3K Inhibitors
文章编号:
20180503
作者:
徐闻曦; 蔡晓然; 郑小娇; 刘根炎; 巨修练*
武汉工程大学化工与制药学院，湖北 武汉 430205
Author(s):
XU Wenxi; CAI Xiaoran; ZHENG Xiaojiao; LIU Genyan; JU Xiulian*
School of Chemical Engineering and Pharmacy， Wuhan Institute of Technology，Wuhan 430205， China
关键词:
肌钙蛋白I相关激酶抑制剂; CoMFA; 分子对接; 虚拟筛选
Keywords:
troponin I-interacting protein kinase inhibitors;  CoMFA;  docking;  virtual screening
分类号:
R917；O641
DOI:
10. 3969/j. issn. 1674-2869. 2018. 05. 003
文献标志码:
A
摘要:
通过一系列肌钙蛋白I相关激酶抑制剂苯磺酰胺衍生物构建了其3D-QSAR模型，研究其结构与活性关系。所得CoMFA、TopomerCoMFA模型的交叉验证相关系数q2分别为0.622、0.768，非交叉验证系数r2分别为0.952、0.981，外部验证相关系数R2pred分别为0.823、0.754，说明模型具有良好的预测性能和稳定性。采用Topomer Search对ZINC数据库进行虚拟筛选，共得到25个分子，其预测活性均高于活性最高的模板分子。最后通过分子对接筛选得到11个分子可作为TNNI3K抑制剂进一步研究。
Abstract:
Three dimensional structure-activity relationships （3D-QSAR） models were constructed with a series of Troponin I-interacting protein Kinase inhibitors benzyl sulfonamide derivatives to investigate the structure-activity relationship. The cross-validate regress coefficients （q2） of CoMFA and TopomerCoMFA were 0.622， 0.768， and the noncross-validate regress coefficients （r2）were 0.952， 0.981， respectively. However， the external validation coefficients（r2pred） of CoMFA and TopomerCoMFA were 0.823， 0.754 respectively， indicating that both models are ?favorable??stable?and?predictable. Moreover， Topomer Search was utilized for virtual screening in ZINC database， and 25 new molecules were obtained， which exhibited higher activity compared with those template molecules. Finally， 11 molecules were screened by molecular docking as the potential inhibitors of TNNI3K.

参考文献/References:

［1］　LAL H， AHMAD F， SHAN P， et al. Troponin I-interacting protein kinase［J］. Circulation Journal， 2014， 78（7）：1514-1519.［2］　ZHAO Y， MENG X M， WEI Y J， et al. Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I［J］. Journal of Molecular Medicine， 2003， 81（5）：297-304.［3］　王银，徐瑞霞. 心肌特异激酶TNNI3K与心血管疾病的关系［J］. 中国分子心脏病学杂志， 2016（1）：1605-1608.［4］　VAGNOZZI R J， JR G J G， KALLANDER L S， et al. Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress， injury， and adverse remodeling in the ischemic heart［J］. Science Translational Medicine， 2013， 207（5）：207ra141.［5］　LAWHORN B G， PHILP J， GRAVES A P， et al. Substituent effects on drug-receptor h-bond interactions： correlations useful for the design of kinase inhibitors［J］. Journal of Medicinal Chemistry， 2016， 59（23）：10629-10641.［6］　CRAMER R D， SOLTANSHAHI F， JILEK R， et al. AllChem：generating and searching 10（20） synthetically accessible structures［J］. Journal of Computer-aided Molecular Design， 2007， 21（6）：341-350.［7］　KIM K H. Comparative molecular field analysis （CoMFA）［M］// Encyclopedia of Computational Chemistry. John Wiley & Sons， Ltd， 2002：291-331.［8］　DEPRIEST S A， MAYER D， NAYLOR C B， et al. 3D-QSAR of angiotensin-converting enzyme and thermolysin inhibitors： a comparison of CoMFA models based on deduced and experimentally determined active site geometries［J］. Journal of the American Chemical Society， 1993， 115（13）：5372-5384.［9］　ZHANG L， TSAI K C， DU L， et al. How to generate reliable and predictive CoMFAmodels［J］. Current Medicinal Chemistry， 2011， 18（6）：923-930.［10］　ROY K， MITRA I. On various metrics used for validation of predictive QSAR models with applications in virtual screening and focused library design［J］. Combinatorial Chemistry & High Throughput Screening， 2011， 14（6）：450-474.［11］　CRAMER R D.TopomerCoMFA：a design methodology for rapid lead optimization［J］. Journal of Medicinal Chemistry， 2003， 46（3）：374-388.［12］　CRAMER R D，CRUZ P，STAHL G，et al. ChemInform abstract：virtual screening for r-groups， including predicted pIC50 contributions， within large structural databases， using topomerCoMFA［J］. Cheminform， 2008， 48（11）：2180-2195.［13］　ZHAO Y， MENG X M， WEI Y J， et al. Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I［J］. Journal of Molecular Medicine，2003，81（5）：297-304.［14］　DHARMENDRA K YADAV，FEROZ K，SRIVASTAVA S K. Docking and QSAR studies of camptothecin derivatives as inhibitor of DNA topoisomerase-I［J］. Journal of Chemometrics， 2013， 27（1/2）：21-33.

相似文献/References:

[1]陈向阳,李健,程瑾,等.新烟碱类结构与活性的CoMFA及CoMSIA研究[J].武汉工程大学学报,2009,(12):11.
　CHEN Xiang yang,LI Jian,CHENG Jin,et al.3DQSAR Analysis of Neonicotinoid Compounds UsingCoMFA and CoMSIA[J].Journal of Wuhan Institute of Technology,2009,(05):11.

备注/Memo

备注/Memo:
收稿日期：2018-03-29作者简介：徐闻曦，硕士研究生。E-mail：15107105737@163com*通讯作者：巨修练，博士，教授，博士研究生导师。E-mail：xiulianju2008@aliyun.com引文格式：徐闻曦，蔡晓然，郑小娇，等. TNNI3K抑制剂3D-QSAR的研究及虚拟筛选［J］. 武汉工程大学学报，2018，40（5）：485-493.
更新日期/Last Update: 2018-10-23