Vistoli Giulio, Pedretti Alessandro, Dei Silvia, Scapecchi Serena, Marconi Cristina, Romanelli Maria Novella
Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Università di Milano, Via Mangiagalli, 25 I-20133 Milano, Italy.
Bioorg Med Chem. 2008 Mar 15;16(6):3049-58. doi: 10.1016/j.bmc.2007.12.036. Epub 2008 Jan 7.
The study presents a docking analysis for the interaction capabilities of some muscarinic receptors (i.e., M(1), M(2), and M(5)) whose full-length models were previously generated by us. In detail, the docking simulations involved a dataset of 30 agonists, taken from the literature, including a first series of oxathiolane/dioxolane congeners and a second subset of more heterogeneous ligands. The obtained results unveil that it is possible to discriminate among the binding modes of considered muscarinic receptors, developing specific interaction patterns which are significantly different for the arrangement of both polar and hydrophobic interactions. Thus, the M(1) subtype possesses the widest binding site, while the M(2) receptor is characterized by a large but asymmetric region that accommodates the ligand's ammonium head and finally the M(5) binding site is quite similar to that of M(2) subtype being univocally characterized by a second aspartate residue which interacts with the ammonium head. The significant correlations between docking scores and affinity values afford an encouraging validation for the reported binding modes and confirm the key role of molecular flexibility in the ligand recognition of muscarinic receptors.
该研究对一些毒蕈碱受体（即M(1)、M(2)和M(5)）的相互作用能力进行了对接分析，这些受体的全长模型此前由我们构建。具体而言，对接模拟涉及从文献中选取的30种激动剂数据集，包括第一系列的氧硫杂环戊烷/二氧戊环同系物以及第二组更为多样化的配体。所得结果表明，能够区分所考虑的毒蕈碱受体的结合模式，形成特定的相互作用模式，这些模式在极性和疏水相互作用的排列上有显著差异。因此，M(1)亚型具有最宽的结合位点，而M(2)受体的特征是有一个大但不对称的区域来容纳配体的铵基头部，最后M(5)结合位点与M(2)亚型相当相似，其独特特征是有第二个与铵基头部相互作用的天冬氨酸残基。对接分数与亲和力值之间的显著相关性为所报道的结合模式提供了令人鼓舞的验证，并证实了分子柔性在毒蕈碱受体配体识别中的关键作用。
