Aricept Complexed with Acetylcholinesterase: Difference between revisions
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<StructureSection load='1eve' size='450' side='right' scene='29/2908/1eve_e20_cartoon/3' caption=''> | |||
[[Image:E2020_interactins_in_AChE_gorge.jpg|left|250px]]<br /> | |||
'''3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase''' | '''3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase''' | ||
(see also [[AChE inhibitors and substrates]]) | |||
==Background== | ==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 3D structure of ''Torpedo californica'' AChE (''Tc''AChE) ([[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. | 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 (''Tc''AChE) ([[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. | ||
{{Clear}} | |||
==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/ | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/7'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/5'>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/E20_interactionshown/8'>indirectly via solvent molecules</scene>. | ||
==Conclusions== | ==Conclusions== | ||
The X-ray | 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 Structure== | ==About this Structure== | ||
1EVE is a | |||
1EVE is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. The June 2004 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Acetylcholinesterase'' by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2004_6 10.2210/rcsb_pdb/mom_2004_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EVE OCA]. | |||
==Additional Resources== | |||
For additional information, see: [[Alzheimer's Disease]]<br /> | |||
<br /> | |||
</StructureSection> | |||
==Reference== | ==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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10368299 10368299] | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10368299 10368299] | ||
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[[Category: Acetylcholinesterase]] | [[Category: Acetylcholinesterase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: neurotransmitter cleavage]] | [[Category: neurotransmitter cleavage]] | ||
[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
[[Category: RCSB PDB Molecule of the Month]] | |||