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| 血管内皮细胞生长因子受体2抑制剂三维药效团模型的构建 |
| 陈军1,2△,黄晶晶1△,郑灿辉1,吕加国1,周有骏1,朱驹1* |
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(1.第二军医大学药学院药物化学教研室,上海 200433;
2.成都军区总医院药剂科,成都 610083
△共同第一作者
*通信作者) |
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| 摘要: |
| 目的 构建血管内皮细胞生长因子受体2(VEGFR-2)抑制剂的三维药效团模型,为设计新型抑制剂建立理论模型。方法 应用Discovery Studio 2.5中的Catalyst模块,选取已确证结合于VEGFR-2活性腔、结合模式一致、抑制活性跨度5个数量级、结构具有多样性的30个抑制剂,其中21个分子作为训练集,余9个分子作为测试集产生三维药效团模型。结果 最优药效团模型由1个氢键受体、2个疏水中心、1个芳环平面和4个排斥体积组成,预测相关性R为0.89。结论 交叉验证结果表明药效团模型具有较好的预测能力,可用于数据库搜索筛选结构新颖的抑制VEGFR-2的先导化合物。 |
| 关键词: 血管内皮生长因子受体2 抑制剂 药效团模型 抗肿瘤 |
| DOI：10.3724/SP.J.1008.2012.00759 |
| 投稿时间：2012-02-24修订日期：2012-05-07 |
| 基金项目:上海市浦江人才计划(09PJ1400300). |
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| Construction of 3D pharmacophore model of vascular endothelial growth factor receptor 2 inhibitors |
| CHEN Jun1,2△, HUANG Jing-jing1△, ZHENG Can-hui1, Lü Jia-guo1, ZHOU You-jun1, ZHU Ju1* |
(1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
2. Department of Pharmacy, General Hospital, PLA Chengdu Military Area Command, Chengdu 610083, Sichuan, China
△Co-first authors.
*Corresponding author.) |
| Abstract: |
| ObjectiveTo construct the three dimensional pharmacophore models of inhibitors of vascular endothelial growth factor receptor 2(VEGFR-2), so as to provide a theoretical model for designing novel VEGFR-2 inhibitors. MethodsThe model was derived from 30 reported VEGFR-2 inhibitors (21 molecules as training set and the rest as testing set)with structural variety and resembling binding mode, whose IC50 values spanned 5 magnitudes by using Catalyst Software in Discovery Studio 2.5 Package. ResultsThe best model consists of one hydrogen bond receptor, two hydrophobic cores, one aromatic plane and 4 excluded volumes. The predictive relativity (R) was 0.89. ConclusionCross-validation results indicate that the constructed model has satisfactory predictivity and can be used to screen molecule databases for searching novel lead compounds which can inhibit VEGFR-2. |
| Key words: vascular endothelial growth factor receptor-2 pharmacophore model antineoplastic agents |
