Building three-dimensional structures of HIV-1 coreceptor CCR5 and its interaction with antagonist TAK779 by comparative molecular modeling  

HIV-共受体CCR5的三维结构及与其拮抗剂TAK 779相互作用的比较分子模拟(英文)

作　　者：黄小琴[1] 蒋华良[1] 罗小民[1] 陈凯先[1] 嵇汝运[1] 曹阳[2] 裴钢[3] 

机构地区：[1]中国科学院上海药物研究所 [2]苏州大学化学系 [3]中国科学院上海细胞生物学研究所

出　　处：《Acta Pharmacologica Sinica》2000年第6期43-50,共8页中国药理学报（英文版）

基　　金：Project supported by the Key Program of National Natural Science Foundation of China (Grants 29790123 and 29725203)

摘　　要：AIM: To study the mechanism of interaction of CCR5 receptor with its antagonist TAK779. METHODS: Comparative molecular modeling has been used to develop the 3D-structural models of CCR5 receptor and its complex with TAK779. Molecular mechanics has been applied to optimize the above molecular models. Quantum mechanics has been utilized to calculate the structural information of TAK779. DOCK4. 0 program is employed to dock the TAK779 molecular into the binding site of CCR5 receptor. RESULTS:The 3D-structural model of CCR5 receptor is constructed using the 3D-mod-el of frog rhodopsin as a template. The binding pocket is situated in the transmembrane helices 3, 5, 6, and 7, and it is composed of conserved residues of Tyr108, Gly111, Ser114, Glu283, Gly286, and Cys290, and conservatively varied residues including Thr105, Leu107, Phe112, Gly115, Lys197, and Met287. O1, N7, N17, and O19 of TAK779 are the active center of TAK779. The pyran cycle and the aminium group of TAK779 interact with residues in the binding pocket of CCR5 receptor, the other part of TAK779 interacts with residues from the extracellular loops of OCR5. The binding energy of TAK779 with CCR5 is - 51. 606 kcal/mol. CONCLUSION: The model constructed and the interaction mode reported in the present study are useful in further understanding the molecular mechanism of receptor-virusrecognition and designing new inhibitors of HTV-1 infection.目的:研究HIV-1的共受体CCR5与其拮抗剂TAK779的相互作用机制。方法:用比较分子模拟方法建立CCR5受体的三维结构模型;通过量子化学计算得到TAK779分子的结构参数和最优几何构型;用DOCK4.0程序将TAJ779分子对接到CCR5受体的结合位点上。结果:通过分子力学优化得到了CCR5受体的三维结构模型,配体的结合口袋位于第三、五、六、七跨膜区,组成结合口袋的氨基酸残基主要为Thr105、Leu107、Tyr108、Gly111、Phe112、Ser114、Gly115、Lys197、Glu283、Gly286、Met287、Cys290;TAK779与CCR5受体的相互作用方式为氢键、静电和疏水作用;配体与受体的结合能为-51.606 kcal/mol。结论:上述模型有助于进一步理解膜受体识别HIV-1病毒的分子机制并设计新的HIV-1抑制剂。

关 键 词：TAK 779 CCR5 receptor molecular structure HIV-1 computer aided design 

分 类 号：R96[医药卫生—药理学]