Nordvall G, Hacksell U
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
J Med Chem. 1993 Apr 16;36(8):967-76. doi: 10.1021/jm00060a003.
A model of the muscarinic m1 receptor has been constructed on the basis of the putative three-dimensional structural similarity between bacteriorhodopsin and G-protein coupled receptors. The homology-based m1 receptor model takes into account hydrophobicity and conserved amino acids and information from site-directed mutagenesis studies and from hydropathy plots. The resulting model was used in conjunction with an indirect model which describes a proposed active agonist conformation of acetylcholine and a number of related compounds. A receptor-excluded volume was constructed by superimposing these muscarinic agonists and calculating their combined van der Waals volume. The resulting m1 receptor excluded volume was used to define the agonist binding site, which consists of nine amino acids and which binds agonists primarily through interaction with Asp105 (ionic interaction). Thr192 and Asn382 (hydrogen bonds). The model is flexible since the conformation of the nine amino acids may change in response to the agonist structure. The combination of indirect and homology-based approaches is particularly attractive since it utilizes more experimental data than a purely homology-based model and since a binding-site model might be more realistic and general in terms of applicability than indirect models. Docking of the ligands was performed by optimizing attractive interactions and minimizing repulsive interactions. In addition to the agonists used to define the binding site, structurally different agonists are also accommodated by the binding-site model. Furthermore, the m1 receptor binding-site model is able to reproduce experimentally determined stereoselectivities.
基于细菌视紫红质与G蛋白偶联受体之间假定的三维结构相似性，构建了毒蕈碱m1受体模型。基于同源性的m1受体模型考虑了疏水性、保守氨基酸以及定点诱变研究和亲水性图谱提供的信息。所得模型与一个间接模型结合使用，该间接模型描述了乙酰胆碱和一些相关化合物的拟活性激动剂构象。通过叠加这些毒蕈碱激动剂并计算它们的组合范德华体积，构建了受体排除体积。所得的m1受体排除体积用于定义激动剂结合位点，该位点由九个氨基酸组成，主要通过与Asp105（离子相互作用）、Thr192和Asn382（氢键）相互作用来结合激动剂。该模型具有灵活性，因为九个氨基酸的构象可能会因激动剂结构而改变。间接方法与基于同源性的方法相结合特别有吸引力，因为它比纯基于同源性的模型利用了更多的实验数据，而且就适用性而言，结合位点模型可能比间接模型更现实、更通用。通过优化吸引相互作用和最小化排斥相互作用来进行配体对接。除了用于定义结合位点的激动剂外，结合位点模型还能容纳结构不同的激动剂。此外，m1受体结合位点模型能够重现实验确定的立体选择性。
