Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain
Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain
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DOI：
10.1016/j.bmc.2012.06.054
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发表时间：
2012-10-01
影响因子：
3.5
通讯作者：
de Esch, Iwan J. P.
中科院分区：
文献类型：
--
作者：
Akdemir, Atilla;Edink, Ewald;de Esch, Iwan J. P.
使用激动剂结合的嵌合α 7/Ls-AChBP蛋白的晶体结构的分级计算机筛选程序成功地应用于含有药物样分子的专有和商业数据库。获得了26%（pK（i）> 5.0）的总体命中率，其中商业化合物收集物的命中率甚至更好，为35%。结构新颖和多样的配体被确定。[H-3]地棘蛙素对嵌合α 7/5-HT 3受体的结合研究产生了亚微摩尔的抑制常数。与以前利用野生型Ls-AChBP晶体结构的筛选程序相比，目前的研究表明，最近获得的α 7/Ls-AChBP嵌合蛋白晶体结构是用于鉴定新型α 7受体配体的更好模板。(C)2012爱思唯尔有限公司保留所有权利。
A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric alpha 7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) > 5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [H-3]epibatidine on chimeric alpha 7/5-HT3 receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained alpha 7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel alpha 7 receptor ligands. (C) 2012 Elsevier Ltd. All rights reserved.