Axe Frank U, Bembenek Scott D, Szalma Sándor
Axe Consulting Services, 14595 Surrey Junction Lane, Sutter Creek, CA 95685, USA.
J Mol Graph Model. 2006 May;24(6):456-64. doi: 10.1016/j.jmgm.2005.10.005. Epub 2005 Dec 28.
Molecular modeling was used to analyze the binding mode and activities of histamine H3 receptor antagonists. A model of the H3 receptor was constructed through homology modeling methods based on the crystal structure of bovine rhodopsin. Known H3 antagonists were interactively docked into the putative antagonist binding pocket and the resultant model was subjected to molecular mechanics energy minimization and molecular dynamics simulations which included a continuum model of the lipid bilayer and intra- and extracellular aqueous environments surrounding the transmembrane helices. The transmembrane helices stayed well embedded in the dielectric slab representing the lipid bilayer and the intra- and extracellular loops remain situated in the aqueous solvent region of the model during molecular dynamics simulations of up to 200 ps in duration. A pharmacophore model was calculated by mapping the features common to three active compounds three-dimensionally in space. The 3D pharmacophore model complements our atomistic receptor/ligand modeling. The H3 antagonist pharmacophore consists of two protonation sites (i.e. basic centers) connected by a central aromatic ring or hydrophobic region. These two basic sites can simultaneously interact with Asp 114 (3.32) in helix III and a Glu 206 (5.46) in helix V which are believed to be the key residues that histamine interacts with to stabilize the receptor in the active state. The interaction with Glu 206 is consistent with the enhanced activity resulting from the additional basic site. In addition to these two salt bridging interactions, the central region of these antagonists contains a lipophilic group, usually an aromatic ring, that is found to interact with several nearby hydrophobic side chains. The picture of antagonist binding provided by these models is consistent with earlier pharmacophore models for H3 antagonists with some exceptions.
分子模拟被用于分析组胺H3受体拮抗剂的结合模式和活性。基于牛视紫红质的晶体结构，通过同源建模方法构建了H3受体模型。将已知的H3拮抗剂与假定的拮抗剂结合口袋进行交互式对接，然后对所得模型进行分子力学能量最小化和分子动力学模拟，其中包括脂质双层以及跨膜螺旋周围的细胞内和细胞外水环境的连续介质模型。在长达200皮秒的分子动力学模拟过程中，跨膜螺旋很好地嵌入代表脂质双层的电介质板中，细胞内和细胞外环仍位于模型的水溶剂区域。通过在空间中三维映射三种活性化合物共有的特征来计算药效团模型。三维药效团模型补充了我们的原子受体/配体建模。H3拮抗剂药效团由两个质子化位点（即碱性中心）组成，它们由一个中心芳香环或疏水区域连接。这两个碱性位点可以同时与螺旋III中的Asp 114（3.32）和螺旋V中的Glu 206（5.46）相互作用，据信这两个残基是组胺与之相互作用以稳定处于活性状态的受体的关键残基。与Glu 206的相互作用与额外碱性位点导致的活性增强一致。除了这两个盐桥相互作用外，这些拮抗剂的中心区域含有一个亲脂性基团，通常是一个芳香环，发现它与几个附近的疏水侧链相互作用。这些模型提供的拮抗剂结合情况与早期H3拮抗剂的药效团模型一致，但有一些例外。
