Identification of a putative binding site for 5-alkyl-benzothiadiazides in the AMPA receptor dimer interface

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• 作者：Kasper Harpsø ; e ; Thomas Varming ; Alex Haahr Gouliaev ; Dan Peters ; Tommy Liljefors
• 关键词：AMPA receptor ; Allosteric modulator ; Docking ; Molecular interaction fields ; Structure– ; activity analysis
• 刊名：Journal of Molecular Graphics and Modelling
• 出版年：2007
• 出版时间：July 2007
• 年：2007
• 卷：26
• 期：1
• 页码：213-225
• 全文大小：1802 K

文摘

Crystal structures of three different allosteric modulators co-crystallized with the iGluR2 ligand-binding domain are currently available. The modulators, cyclothiazide, aniracetam and CX614, bind at overlapping binding sites in the dimer interface between two iGluR2 subunits. However, pharmacological data indicate that there are one or more additional binding sites for this class of compounds. Based on differences in structure–activity relationship data we show that 5-alkyl-benzothiadiazide (5ABTD) modulators and a series of close analogs of cyclothiazide, despite having a common core structure, do not have the same binding site. In the present work, a new potential binding site for allosteric modulators has been identified in the dimer interface of the iGluR2 ligand-binding domain. By comparing different iGluR2 crystal structures including different co-crystallized agonists, this cavity is shown to be a structurally conserved part of the dimer interface. The cavity is characterized with respect to shape and potential favorable interactions with ligands and docking is used to find a reasonable binding mode for the core structure of the 5ABTDs. The extensive structure–activity data available for this series of compounds are in agreement with the proposed binding mode, supporting the conclusion that the identified cavity most likely is the binding site for the 5ABTDs.