Aricept Complexed with Acetylcholinesterase: Difference between revisions
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==Overview== | ==Overview== | ||
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). 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: 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 (W84) 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., CONCLUSIONS: 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. | 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). 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: 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., CONCLUSIONS: 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 Structure== | ==About this Structure== | ||