The Crystal Structure of a Complex of Acetylcholinesterase with a Bis-(−)-nor-meptazinol Derivative Reveals Disruption of the Catalytic Triad

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• 作者：Aviv Paz ; Qiong Xie ; Harry M. Greenblatt ; Wei Fu ; Yun Tang ; Israel Silman ; Zhuibai Qiu ; Joel L. Sussman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2543-2549
• 全文大小：359K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

A bis-(−)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Aβ peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 Å resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the “anionic” subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N^ε2, which is hydrogen-bonded to Ser200O^γ in the native enzyme. The second nor-meptazinol binds at the peripheral “anionic” site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(−)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.