Aricept Complexed with Acetylcholinesterase: Difference between revisions
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==Results== | ==Results== | ||
The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/3'>unique orientation</scene>, along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/1'>W84</scene>) of the, active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/1'>near W279</scene>), 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. | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/3'>unique orientation</scene>, along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/1'>W84</scene>) of the, active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/1'>near W279</scene>), 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 <scene name='1eve/E2020_interaction/1'>indirectly via solvent molecules</scene>. | ||
==Conclusions== | ==Conclusions== | ||
Revision as of 18:46, 1 February 2008
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3D Structure of anti-Alzheimer's drug, E2020 (ARICEPT), complexed with its target acetylcholinesterase
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). 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.
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 struture 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 Single protein structure of sequence from Torpedo californica with NAG and E20 as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Known active sites: CAT and IHB. Full crystallographic information is available from OCA.
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
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