Aricept Complexed with Acetylcholinesterase
From Proteopedia
3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase (see also AChE inhibitors and substrates)
BackgroundSeveral 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 3D structure of Torpedo californica AChE (TcAChE) (1ea5). 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. ResultsThe X-ray structure of the E2020-TcAChE complex shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite (W84) of the active site, at the bottom, to the peripheral anionic site (near W279), 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. ConclusionsThe X-ray structure shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE, to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles. About this Structure1EVE is a 1 chain structure with sequence from Torpedo californica. The June 2004 RCSB PDB Molecule of the Month feature on Acetylcholinesterase by David S. Goodsell is 10.2210/rcsb_pdb/mom_2004_6. Full crystallographic information is available from OCA. Additional ResourcesFor additional information, see: Alzheimer's Disease
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Reference
Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs., Kryger G, Silman I, Sussman JL, Structure. 1999 Mar 15;7(3):297-307. PMID:10368299
Proteopedia Page Contributors and Editors (what is this?)
Eran Hodis, Joel L. Sussman, Jaime Prilusky, Alexander Berchansky, OCA, Michal Harel, David Canner, Wayne Decatur, Pham Ngoc Phuong, Angel Herraez, Lucie Kolarova