Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-Alzheimer drug ganstigmine (CHF-2819)
Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-Alzheimer drug ganstigmine (CHF-2819)
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DOI：
10.1021/jm060293s
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发表时间：
2006-08-24
影响因子：
7.3
通讯作者：
Lamba, Doriano
中科院分区：
文献类型：
--
作者：
Bartolucci, Cecilia;Siotto, Mariacristina;Lamba, Doriano
甘斯的明是一种口服活性的、基因工程衍生的、基于氨基甲酸酯的乙酰胆碱酯酶抑制剂，用于治疗阿尔茨海默病。在2.40埃分辨率下测定了更斯的明与加利福尼亚电鳐乙酰胆碱酯酶（TcAChE）偶联物的晶体结构，并对更斯的明和新的基因工程衍生物的体外和离体抗AChE活性进行了详细的基于结构的分析。氨基甲酰基部分共价结合到活性位点丝氨酸，而离去基团geneseroline不保留在催化口袋中。更斯的明的氨基甲酰基部分的氮原子与活性位点组氨酸（His440）进行关键的氢键相互作用。这一结果为催化三联体的失活提供了解释，并可能解释了更斯的明在体内的作用持续时间长。3D结构还为设计具有改善的结合亲和力和药理学性质的化合物提供了结构框架。
Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 angstrom resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.