[1]罗海彬,陈国文,邵咏贤,等.嘧啶类CDK1激酶抑制剂的三维定量构效关系[J].深圳大学学报理工版,2012,29(No.5(377-470)):438-443.[doi:10.3724/SP.J.1249.2012.05438]
 LUO Hai-bin,CHEN Guo-wen,SHAO Yong-xian,et al.3D-QSAR studies on pyrimidine analogues as cyclin-dependent kinase 1 inhibitors[J].Journal of Shenzhen University Science and Engineering,2012,29(No.5(377-470)):438-443.[doi:10.3724/SP.J.1249.2012.05438]
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嘧啶类CDK1激酶抑制剂的三维定量构效关系()
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《深圳大学学报理工版》[ISSN:1000-2618/CN:44-1401/N]

卷:
第29卷
期数:
2012年No.5(377-470)
页码:
438-443
栏目:
化学与化工
出版日期:
2012-09-21

文章信息/Info

Title:
3D-QSAR studies on pyrimidine analogues as cyclin-dependent kinase 1 inhibitors
作者:
罗海彬 陈国文 邵咏贤 李哲 刘明 刘培庆
中山大学药学院, 广州 510006
Author(s):
LUO Hai-bin CHEN Guo-wen SHAO Yong-xian LI Zhe LIU Ming and LIU Pei-qing
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P.R.China
关键词:
药物化学 药物分子设计 三维定量构效关系 1型细胞周期蛋白依赖性激酶 抑制剂 肿瘤治疗
Keywords:
medicinal chemistry drug design three dimensional quantitative structure-activity relationships (3D-QSAR) cyclin-dependent kinase 1(CDK1) inhibition cancer treatment
分类号:
R 914.2; TP 183
DOI:
10.3724/SP.J.1249.2012.05438
文献标志码:
A
摘要:
1型细胞周期蛋白依赖性激酶(cyclin-dependent kinase 1, CDK1)在人体内是有效的抗癌作用靶标.使用三维定量构效关系研究方法,包括比较分子场分析法 (comparative molecular field analysis, CoMFA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis, CoMSIA),分析23个CDK1激酶抑制剂的分子结构与生物活性之间的定量关系.相对其他类型电荷,当训练集加载Gasteiger-Huckel电荷时,CoMFA获得一个最优的三维定量构效关系模型,其交叉验证系数q2为0.668,非交叉验证相关系数R2为0.941,表明模型具有较好的预测能力.使用测试集交叉验证说明该模型稳定可靠,模型中立体场贡献率为69.8%,静电场贡献率为30.2%.
Abstract:
Cyclin-dependent kinases(CDKs) are serine/threonine kinases, which play significant roles in cell cycle regulation. CDK1 is an anti-cancer target among these CDKs. To identify the quantitative relationships between the molecular structures and their biological affinities of twenty-three CDK1 inhibitors, three dimensional quantitative structure-activity relationships (3D-QSAR) studies were performed by using the comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) approaches. In the present study, a reasonable CoMFA Region Focus model with the combined steric and electrostatic fields achieved the highest q2 value(q2=0.668, which R2=0.941). This focus model is adequate to account for the inhibitory mechanisms of these inhibitors. The resulting model was further validated by the test-set examinations. In this model, the contributions of the steric and electrostatic fields were 69.8% and 30.2%, respectively. The results contribute to the rational molecular design of new 2-amino-4-(7-azaindol-3-yl)pyrimidines derivatives with high inhibitory affinities towards CDK1.

参考文献/References:

[1] Murray A W. Recycling the cell cycle: cyclins revisited[J]. Cell, 2004, 116(2): 221-234.
[2] Gibbs J B. Mechanism-based target identification and drug discovery in cancer research[J]. Science, 2000, 287(5460): 1969-1973.
[3] Jain S K, Bharate S B, Vishwakarma R A. Cyclin-dependent kinase inhibition by flavoalkaloids[J]. Mini-reviews in Medicinal Chemistry, 2012, 12(7): 632-649.
[4] Dickson M A, Schwartz G K. Development of cell-cycle inhibitors for cancer therapy[J]. Current Oncology, 2009, 16(2): 36-43.
[5] Huwe A, Mazitschek R, Giannis A. Small molecules as inhibitors of cyclin-dependent kinases[J]. Angewandte Chemie International Edition, 2003, 42(19): 2122-2138.
[6] Wang Q, Su L, Liu N, et al. Cyclin dependent kinase 1 inhibitors: a review of recent progress[J]. Current Medicinal Chemistry, 2011, 18(13): 2025-2043.
[7] Kim K S, Sack J S, Tokarski J S, et al. Thio-and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects[J]. Journal of Medicinal Chemistry, 2000, 43(22): 4126-4134.
[8] Arris C E, Boyle F T, Calvert A H, et al. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles[J]. Journal of Medicinal Chemistry, 2000, 43(15): 2797-2804.
[9] Fang J, Huang D, Zhao W, et al. A new protocol for predicting novel GSK-3β ATP competitive inhibitors[J]. Journal of Chemical Information & Modeling, 2011, 51(6): 1431-1438.
[10] Liu M, He L, Hu X, et al. 3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor[J]. Bioorganic & Medicinal Chemistry Letters, 2010, 20(23): 7004-7010.
[11] Bhatt H G, Patel P K. Pharmacophore modeling, virtual screening and 3D-QSAR studies of 5-tetrahydroquinolinylidine aminoguanidine derivatives as sodium hydrogen exchanger inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2012, 22(11): 3758-3765.
[12] Fortin S, Wei L, Moreau E, et al. Design, synthesis, biological evaluation, and structure-activity relationships of substituted phenyl 4-(2-oxoimidazolidin-1-yl) benzenesulfonates as new tubulin inhibitors mimicking combretastatin A-4[J]. Journal of Medicinal Chemistry, 2011, 54(13): 4559-4580.
[13] Mao Y, Lin N, Tian W, et al. Design, synthesis, and biological evaluation of new diaminoquinazolines as β-catenin/Tcf4 pathway inhibitors[J]. Journal of Medicinal Chemistry, 2012, 55(3): 1346-59.
[14] Baraldi P G, Baraldi S, Saponaro G, et al. Novel 1,3-dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol- 5-yl)xanthines as potent and selective A2 B adenosine receptor antagonists[J]. Journal of Medicinal Chemistry, 2012, 55(2): 797-811.
[15] Caballero J, Fernández M, González-Nilo F D. Structural requirements of pyrido[2,3-d]pyrimidin-7-one as CDK4/D inhibitors: 2D autocorrelation, CoMFA and CoMSIA analyses[J]. Bioorganic & Medicinal Chemistry. 2008, 16(11): 6103-6115.
[16] Huang S, Li R, Connolly P J, et al. Synthesis of 2-amino-4-(7-azaindol-3-yl)pyrimidines as cyclin dependent kinase 1 (CDK1) inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2006,16(18): 4818-4821.
[17] Al-Sha’er M A, Taha M O. Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay[J]. European Journal of Medicinal Chemistry, 2010, 45(9): 4316-4330.

备注/Memo

备注/Memo:
Received:2011-10-21;Revised:2012-02-11;Accepted:2012-04-26
Foundation:National Natural Science Foundation of China (21103234); Natural Science Foundation of Guangdong Province (S2011030003190)
Corresponding author:Professor LUO Hai-bin. E-mail:luohb77@mail.sysu.edu.cn
Citation:LUO Hai-bin, CHEN Guo-wen, SHAO Yong-xian, et al. 3D-QSAR studies on pyrimidine analogues as cyclin-dependent kinase 1 inhibitors[J]. Journal of Shenzhen University Science and Engineering, 2012, 29(5): 438-443.(in Chinese)
基金项目:国家自然科学基金资助项目(21103234);广东省自然科学基金资助项目(S2011030003190)
作者简介:罗海彬(1977-),男(汉族),福建省连城县人,中山大学教授. E-mail:luohb77@mail.sysu.edu.cn
引文:罗海彬, 陈国文,邵咏贤,等. 嘧啶类CDK1激酶抑制剂的三维定量构效关系[J]. 深圳大学学报理工版,2012,29(5):438-443.
更新日期/Last Update: 2012-09-26