Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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Modeling the Interactions Between α1-Adrenergic Receptors and Their Antagonists

Author(s): Lupei Du, Minyong Li.

Abstract:

As crucial members of the G-protein coupled receptor (GPCR) superfamily, α1-adrenergic receptors (α1-ARs) are recognized to intervene the actions of endogenous catecholamines such as norepinephrine and epinephrine. So far three distinct α1-AR subtypes, α1A, α1B and α1D, have been characterized by functional analysis, radio-ligand binding and molecular biology studies. The α1-ARs are of therapeutic interest because of their distinct and critical roles in many physiological processes, containing hypertension, benign prostatic hyperplasia, smooth muscle contraction, myocardial inotropy and chronotropy, and hepatic glucose metabolism. Accordingly, designing subtype-selective antagonists for each of the three α1-AR subtypes has been an enthusiastic region of medicinal research. Even though a large number of studies on GPCRs have been conducted, understanding of how known antagonists bind to α1-ARs still remains sketchy and has been a serious impediment to search for potent and subtype-selective α1-AR antagonists because of the lack of detailed experimental structural knowledge. This review deliberates the simulation of α1-ARs and their interactions with antagonists by using ligand-based (pharmacophore identification and QSAR modeling) and structure-based (comparative modeling and molecular docking) approaches. Combined with experimental data, these computational attempts could improve our understanding of the structural basis of antagonist binding and the molecular basis of receptor activation, thus offering a more reasonable approach in the design of drugs targeting α1-ARs.

Keywords: Molecular modeling, pharmacophore, homology modeling, molecular docking, α1-adrenergic receptors (α1-ARs)

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Article Details

VOLUME: 6
ISSUE: 3
Year: 2010
Page: [165 - 178]
Pages: 14
DOI: 10.2174/157340910791760082
Price: $58