Title : Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs - Kryger_1999_Structure_7_297 |
Author(s) : Kryger G , Silman I , Sussman JL |
Ref : Structure , 7 :297 , 1999 |
Abstract :
BACKGROUND:
Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range.
RESULTS:
Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules.
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PubMedSearch : Kryger_1999_Structure_7_297 |
PubMedID: 10368299 |
Gene_locus related to this paper: torca-ACHE |
Inhibitor | Aricept~Donepezil~E2020 |
Gene_locus | torca-ACHE |
Structure | 1EVE |
Kryger G, Silman I, Sussman JL (1999)
Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs
Structure
7 :297
Kryger G, Silman I, Sussman JL (1999)
Structure
7 :297