Tuccinardi Tiziano, Calderone Vincenzo, Rapposelli Simona, Martinelli Adriano
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
J Med Chem. 2006 Jul 13;49(14):4305-16. doi: 10.1021/jm060338p.
A three-dimensional model of the AT1 receptor was constructed by means of a homology modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template and taking into account the available site-directed mutagenesis data. The docking of losartan and its active metabolite EXP3174, followed by 1 ns of molecular dynamics (MD) simulation inserted into the phospholipid bilayer, suggested a different binding orientation for these antagonists from those previously proposed. Furthermore, the docking of several non-peptide antagonists was used as an alignment tool for the development of a three-dimensional quantitative structure-activity relationship (3D-QSAR) model, and the good results confirmed our binding hypothesis and the reliability of the model.
通过同源建模程序构建了AT1受体的三维模型，以牛视紫红质的X射线结构作为初始模板，并考虑了可用的定点诱变数据。将氯沙坦及其活性代谢物EXP3174进行对接，随后在磷脂双层中进行1纳秒的分子动力学（MD）模拟，结果表明这些拮抗剂的结合方向与先前提出的不同。此外，几种非肽拮抗剂的对接被用作开发三维定量构效关系（3D-QSAR）模型的比对工具，良好的结果证实了我们的结合假设以及该模型的可靠性。
