Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors

被引：24

作者：

Akdemir, Atilla ^{[1
]}

Rucktooa, Prakash ^{[2
]}

Jongejan, Aldo ^{[1
]}

van Elk, Rene ^{[3
]}

Bertrand, Sonia ^{[4
]}

Sixma, Titia K. ^{[2
]}

Bertrand, Daniel ^{[4
]}

Smit, August B. ^{[3
]}

Leurs, Rob ^{[1
]}

de Graaf, Chris ^{[1
]}

de Esch, Iwan J. P. ^{[1
]}

机构：

[1] Vrije Univ Amsterdam, Fac Sci, Div Med Chem, LACDR, Amsterdam, Netherlands

[2] Netherlands Canc Inst, Div Biochem, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Fac Earth & Life Sci, Inst Neurosci, Dept Mol & Cellular Neurobiol, Amsterdam, Netherlands

[4] Ctr Med Univ Geneva, Dept Neurosci, Geneva, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 20期

关键词：

Nicotinic acetylcholine receptors (nAChR); Acetylcholine binding protein (AChBP); Electrophysiology; In silico screening; Virtual screening; Docking; Crystallization; Ligand-gated ion channels (LGICs); Cys-loop receptors; X-RAY-STRUCTURE; CRYSTAL-STRUCTURE; MOLECULAR RECOGNITION; EXTRACELLULAR DOMAIN; AGONIST-BINDING; ANTIDEPRESSANTS; ANTAGONISTS; REVEALS; DOCKING; TARGET;

D O I：

10.1016/j.bmc.2011.08.028

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：

Hierarchical in silico screening protocols against the agonist bound acetylcholine binding protein (AChBP) crystal structure were efficient in identifying novel chemotypes for AChBP and the human alpha 7 receptor. Two hit structures were cocrystallized with AChBP revealing intermolecular cation-pi interactions with loop C but lacking intermolecular hydrogen bonding. The compounds act as competitive alpha 7 receptor antagonists and as non-competitive alpha 4 beta 2 receptor inhibitors. These results underline the usability of AChBP in structure-based in silico screening strategies in finding novel scaffolds for the alpha 7 receptor, but also illustrates some limitations of using AChBP as bait to find competitive alpha 4 beta 2 receptor ligands and alpha 7 receptor agonists. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6107 / 6119

页数：13

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