Department of Chemistry, University of Patras , GR-26504, Rion, Patras, Greece.
J Chem Inf Model. 2013 Nov 25;53(11):2874-83. doi: 10.1021/ci400400m. Epub 2013 Oct 25.
The ligand binding determinants for the angiotensin II type 1 receptor (AT1R), a G protein-coupled receptor (GPCR), have been characterized by means of computer simulations. As a first step, a pharmacophore model of various known AT1R ligands exhibiting a wide range of binding affinities was generated. Second, a structural model of AT1R was built making use of the growing set of crystal structures of GPCRs, which was further used for the docking of the AT1R ligands based on the devised pharmacophore model. Next, ligand-receptor-lipid bilayer systems were studied by means of molecular dynamics (MD) simulations. Overall, the present study has permitted, combining the pharmacophore model with binding free energy calculations obtained from the MD simulations, to propose the molecular mechanisms by which sartans interact with AT1R.
计算机模拟已经确定了血管紧张素 II 型 1 受体（AT1R）的配体结合决定因素，AT1R 是一种 G 蛋白偶联受体（GPCR）。作为第一步，生成了具有广泛结合亲和力的各种已知 AT1R 配体的药效团模型。其次，利用越来越多的 GPCR 晶体结构构建了 AT1R 的结构模型，并进一步基于设计的药效团模型对 AT1R 配体进行对接。接下来，通过分子动力学（MD）模拟研究了配体-受体-脂双层系统。总的来说，本研究通过将药效团模型与 MD 模拟获得的结合自由能计算相结合，提出了沙坦类药物与 AT1R 相互作用的分子机制。
