|本期目录/Table of Contents|

[1]魏会宇,等.SHP-2抑制剂药效团模型的构建与应用[J].天津医科大学学报,2015,21(03):25-28.
　WEI Hui-yu,JIN Yuan-yuan,WANG Mei-yan,et al.Construction and application of pharmacophore model of SHP-2 inhibitors[J].Journal of Tianjin Medical University,2015,21(03):25-28.
点击复制

SHP-2抑制剂药效团模型的构建与应用(PDF)
分享到：

《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:
21卷
期数:
2015年03期
页码:
25-28
栏目:
基础医学
出版日期:
2015-05-20

文章信息/Info

Title:
Construction and application of pharmacophore model of SHP-2 inhibitors
文章编号:
1006-8147（2015）0-0025-04
作者:
魏会宇1;  2;  金媛媛2;  王梅燕2;  朱立勤2; 3*
( 1.天津医科大学眼科医院药剂科, 天津医科大学眼视光学院, 天津医科大学眼科研究所, 天津 300384;2.天津医科大学药学院, 天津 300070;3.天津市第一中心医院药学部, 天津 300192)
Author(s):
WEI Hui-yu1; 2;  JIN Yuan-yuan2;  WANG Mei-yan2;  ZHU Li-qin2; 3
(1. Department of Pharmacy，Eye Hospital, Tianjin Medical University, School of Optometry and Ophthalmology, Tianjin Medical University, Eye Institute, Tianjin Medical University, Tianjin 300384, China; 2. School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; 3. Department of Pharmacy, Tianjin First Central Hospital, Tianjin 300192, China)
关键词:

计算机辅助药物设计 ;  药效团模型;  SHP-2抑制剂

Keywords:
computer aided drug design;  pharmacophore model;  SHP-2 inhibitors
分类号:
R914.2
DOI:
-
文献标志码:
A
摘要:
目的：构建并应用蛋白酪氨酸磷酸酶 SHP-2抑制剂药效团模型。方法：应用 Discovery Studio 3.5 软件包中的基于分子共同特征 HipHop 和基于配体-受体晶体复合物 CPB 两种算法构建出 SHP-2抑制剂药效团模型，应用Receiver-operating curve (ROC)分析方法对产生的药效团模型进行验证并对ZINC数据库进行筛选，最后应用 Schrodinger Suite 2009 中的 Qikprop 模块来预测这些化合物的吸收、分布、代谢、排泄的性质，并与已报道的部分化合物作比较。结果：应用 HipHop 和 CPB 两种算法分别得到了识别活性与非活性分子能力最强的药效团模型，并且通过这两个模型筛选出了35个潜在SHP-2抑制活性的化合物，通过 ADME 预测得出设计出的化合物具有较好的ADME性质。结论：此两种药效团模型可以用于后续 SHP-2小分子药物的筛选和优化，同时采用两种药效团联合筛选的方法为计算机辅助药物设计提供了一个新的思路。
Abstract:
Objective: To construct pharmacophore model of SHP-2 inhibitors. Methods: Pharmacophore model of SHP-2 inhibitors was developed using 3D-QSAR

pharmacophore program of HipHop and CPB in Discovery Studio 3.5, and the validation was performed using ROC. Then pharmacophore-based virtual screening for ZINC database was applied. Finally, ADME was performed to predict properties including absorption, distribution, metabolism and excretion, which were compared with corresponding properties of reported compounds. Results: According to the program of HipHop and CPB, the pharmacophore models with the highest recognition ability between the active and non-active molecules were selected as the optimal pharmacophore models, and 35 potential inhibitors of SHP-2 were obtained. Compared with the reported SHP-2 inhibitors, these compounds showed greater potentials to function as drugs during ADME prediction. Conclusion: These two pharmacophore models can contribute to the discovery and design of new SHP-2 inhibitors. Moreover, the screening of combination of the two pharmacophore models provides a new perspective for computer aided drug design.

参考文献/References:

[1]Poole A W, Jones M L. A SHPing tale: Perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail[J]. Cell Signal, 2005,17(11):1323
[2]QU,Cheng K. The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions[J]. Cell Res, 2000,10(4):279
[3]Zheng H, Alter S, Qu C K. SHP-2 tyrosine phosphatase in human diseases[J]. Int J Clin Exp Med,2009,2(1):17
[4]Chan G, Kalaitzidis D, Neel B G. The tyrosine phosphatase Shp2 (PTPN11) in cancer[J]. Cancer Metastasis Rev ,2008,27(2):179
[5]Loh M L. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia[J]. Br J Haematol, 2011,152(6):677
[6]Stuible M, Doody K M, Tremblay M L. PTP1B and TC-PTP: regulators of transformation and tumorigenesis[J].Cancer Metastasis Rev ，2008,27(2):215
[7]Lee J Y, Kim J K, Cho M C, et al. Cytotoxic flavonoids as agonists of peroxisome proliferator-activated receptor on human cervical and prostate cancer cells[J]. J Nat Prod ,2010,73(7):1261
[8]Yu Z H, Chen L, Wu L, et al. Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening[J]. Bioorg Med Chem Lett, 2011,21(14):4238
[9]Liu W, Yu B, Xu G, et al. Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11)[J]. J Med Chem, 2013,56(18):7212
[10]Yu B, Liu W, Yu W M, et al.Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-Associated malignancies[J]. Mol Cancer Ther, 2013,12(9):1738
[11]Duan Y Q, Ma Y, Wang X J, et al. Design potential selective inhibitors for treating Cancer by targeting the Src homology 2 (SH2) domain-containing phosphatase 2 (Shp2) with core hopping approach[J]. Protein Pept LettSee comment in PubMed Commons below, 2014,21(6):556
[12]Bhattarai B R, Shresthaa S, Ham S W, et al. 2-O-Carboxymethylpyrogallol derivatives as PTP1B inhibitors with antihyperglycemic activity[J]. Bioorg Med Chem Lett, 2007,17(19):5357
[13]Shrestha S, Bhattarai B R, Chang K J, et al. Methylenedisalicylic acid derivatives: new PTP1B inhibitors that confer resistance to diet-induced obesity[J]. Bioorg Med Chem Lett, 2007,17(10):2760

相似文献/References:

[1]魏会宇,等.SHP-2抑制剂药效团模型的构建与应用[J].天津医科大学学报,2015,21(01):25.
　WEI Hui-yu,JIN Yuan-yuan,WANG Mei-yan,et al.Construction and application of pharmacophore model of SHP-2 inhibitors[J].Journal of Tianjin Medical University,2015,21(03):25.

备注/Memo

备注/Memo:

基金项目 国家自然科学基金资助项目 (81273361)

作者简介 魏会宇 (1979-)，男，硕士在读，研究方向：新药研究；通信作者：朱立勤，E-mail: zlq0713@aliyun.com。

更新日期/Last Update: 2015-01-22