Aricept Complexed with Acetylcholinesterase

3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase (see also AChE bivalent inhibitors (Part II))

spinqualitylabelsall models PDB ID 1eve Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1eve, resolution 2.50Å ()
Ligands:	,
Activity:	Acetylcholinesterase, with EC number 3.1.1.7
Structural annotation: Resources: CATH : 1Eve000 InterPro : Ipr000908, Ipr002018, Ipr000997 Pfam : PF00135 SCOP : d1eve__ UniProt : P04058
Functional annotation: Cellular component: synapse cell junction membrane Biological process: neurotransmitter catabolic process acetylcholine catabolic process in synaptic cleft Molecular function: cholinesterase activity hydrolase activity GPI anchor binding acetylcholinesterase activity
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

BackgroundBackground

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 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.

spinqualitylabelsall models PDB ID 1eve.pdb Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

ResultsResults

The X-ray structure of the E2020-TcAChE complex shows that E2020 has a 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 .

ConclusionsConclusions

The 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 StructureAbout this Structure

1EVE 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 ResourcesAdditional Resources

For additional information, see: Alzheimer's Disease

ReferenceReference

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

See 1eve (Chinese), 1eve (French), 1eve (Arabic), 1eve (Russian), 1eve (Spanish), & 1eve (Turkish).