School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
J Mol Model. 2010 Sep;16(9):1529-37. doi: 10.1007/s00894-010-0666-z. Epub 2010 Feb 24.
It is widely acknowledged that the H(1) receptor antagonists have important therapeutic significance in the treatment of various allergic disorders, but little was known about the binding mode between the receptor and antagonists since the crystal structure of G-protein coupling receptors (GPCRs) were hard to obtain. In this paper, a theoretical three-dimensional model of human histamine H(1) receptor (HHR1) was developed on the basis of recently reported high resolution structures of human A(2A) adenosine receptor, human beta(2)-adrenoceptor and turkey beta(1)-adrenoceptor. Furthermore, three representative H(1) receptor antagonists were chosen for docking studies. Subsequently, a qualitative pharmacophore model was developed by Hiphop algorithm based on the docking conformations of these three antagonists. In this paper, active environment, certain key residues, and the corresponding pharmacophore features of H(1) receptor were identified by such combinations of receptor-based and ligand-based approaches, which would give sufficient guidance for the rational design of novel antihistamine agents.
人们普遍认为 H（1）受体拮抗剂在治疗各种过敏疾病方面具有重要的治疗意义，但由于 G 蛋白偶联受体（GPCR）的晶体结构难以获得，因此人们对受体和拮抗剂之间的结合模式知之甚少。在本文中，我们基于最近报道的高分辨率人 A（2A）腺苷受体、人β（2）-肾上腺素受体和火鸡β（1）-肾上腺素受体结构，建立了人组氨酸 H（1）受体（HHR1）的理论三维模型。此外，选择了三种具有代表性的 H（1）受体拮抗剂进行对接研究。随后，基于这三种拮抗剂的对接构象，我们使用 Hiphop 算法开发了一个定性的药效团模型。在本文中，我们通过基于受体和基于配体的方法的组合，确定了 H（1）受体的活性环境、某些关键残基和相应的药效团特征，这将为新型抗组胺药物的合理设计提供充分的指导。
