期刊
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
卷 16, 期 7, 页码 511-520出版社
KLUWER ACADEMIC PUBL
DOI: 10.1023/A:1021275430021
关键词
5-HT2A receptor; G-protein coupled receptor; ligand binding; molecular dynamics; receptor activation
资金
- NIDA NIH HHS [DA02189] Funding Source: Medline
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.
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