A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor

被引：47

作者：

Chambers, JJ ^{[1
]}

Nichols, DE ^{[1
]}

机构：

[1] Purdue Univ, Dept Med Chem & Mol Pharmacol, Sch Pharm & Pharmacal Sci, W Lafayette, IN 47907 USA

来源：

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN | 2002年 / 16卷 / 07期

关键词：

5-HT2A receptor; G-protein coupled receptor; ligand binding; molecular dynamics; receptor activation;

D O I：

10.1023/A:1021275430021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A homology-based model of the 5-HT2A receptor was produced utilizing an activated form of the bovine rhodopsin (Rh) crystal structure [1,2]. In silico activation of the Rh structure was accomplished by isomerization of the 11-cis-retinal (1) chromophore, followed by constrained molecular dynamics to relax the resultant high energy structure. The activated form of Rh was then used as a structural template for development of a human 5-HT2A receptor model. Both the 5-HT2A receptor and Rh are members of the G-protein coupled receptor (GPCR) super-family. The resulting homology model of the receptor was then used for docking studies of compounds representing a cross-section of structural classes that activate the 5-HT2A receptor, including ergolines, tryptamines, and amphetamines. The ligand/receptor complexes that ensued were refined and the final binding orientations were observed to be compatible with much of the data acquired through both diversified ligand design and site directed mutagenesis.

引用

页码：511 / 520

页数：10

共 36 条

[1] Mapping the binding site pocket of the serotonin 5-hydroxytryptamine(2A) receptor - Ser(3.36(159)) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin [J].