Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.
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.


CONCLUSIONS
Our study 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.
Kryger
G
G
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Gitay.Kryger@Weizmann.ac.il
Silman
I
I
Sussman
J L
JL
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D000077265:Donepezil; D015195:Drug Design; D007189:Indans / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry* / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D012997:Solvents; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014101:Torpedo
D002800:Cholinesterase Inhibitors; D007189:Indans; D046911:Macromolecular Substances; D018697:Nootropic Agents; D010880:Piperidines; D012997:Solvents; D000077265:Donepezil; D000110:Acetylcholinesterase