Jöhren Kirstin, Höltje Hans-Dieter
Institute for Pharmaceutical Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
J Comput Aided Mol Des. 2002 Nov;16(11):795-801. doi: 10.1023/a:1023880611709.
The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.
M2毒蕈碱型乙酰胆碱受体属于视紫红质样G蛋白偶联受体家族。这种毒蕈碱受体亚型特别受关注，因为除了一个正构结合位点外，它还具有一个别构结合位点。基于牛视紫红质的X射线结构，构建了人M2受体的完整同源模型。对于正构结合位点，有不同激动剂和拮抗剂的点突变及结合研究。这些知识被用于对M2模型的初步验证。活性的别构调节由结构不同的配体介导，如加拉明、卡拉库林V盐或W84（一种六甲铵衍生物）。使用GRID场对接了对M2具有不同亲和力的卡拉库林V衍生物。随后的分子动力学模拟基于不同的静电和脂溶性相互作用产生了不同的结合能。计算得到的亲和力与实验测定的亲和力高度一致。
