On the applicability of GPCR homology models to computer-aided drug discovery:: A comparison between in silico and crystal structures of the β2-adrenergic receptor
On the applicability of GPCR homology models to computer-aided drug discovery:: A comparison between in silico and crystal structures of the β2-adrenergic receptor
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DOI：
10.1021/jm800044k
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发表时间：
2008-05-22
影响因子：
7.3
通讯作者：
Costanzi, Stefano
中科院分区：
文献类型：
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作者：
Costanzi, Stefano
β（2）-肾上腺素能受体（β（2）-AR）晶体结构的发表证明G蛋白偶联受体（GPCR）共享结构保守的视紫红质样7 TM核心。在这里，为了探测在何种程度上可以通过建模重建现实的GPCR结构，将卡拉唑醇对接在两个基于视紫红质的人类β（2）-AR同源模型上。第一个功能的视紫红质样的第二个细胞外环，干扰配体对接和结合口袋中的几个残基的方向。第二个特征是完全从头构建的第二个细胞外环，这提供了更准确的结合口袋模型和更好的配体对接。此外，通过校正排列在结合口袋-Phe 290（6.52）-中的单个残基的构象，将可用的生物化学和计算数据并入模型，导致显著改善的对接姿势。这些结果支持GPCR建模的定点诱变实验的设计和药物发现的适用性。
The publication of the crystal structure of the beta(2)-adrenergic receptor (beta(2)-AR) proved that G protein-coupled receptors (GPCRs) share a structurally conserved rhodopsin-like 7TM core. Here, to probe to which extent realistic GPCR structures can be recreated through modeling, carazolol was docked at two rhodopsin-based homology models of the human beta(2)-AR. The first featured a rhodopsin-like second extracellular loop, which interfered with ligand docking and with the orientation of several residues in the binding pocket. The second featured a second extracellular loop built completely de novo, which afforded a more accurate model of the binding pocket and a better docking of the ligand. Furthermore, incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket -Phe290(6.52)-, resulted in significantly improved docking poses. These results support the applicability of GPCR modeling to the design of site-directed mutagenesis experiments and to drug discovery.