Aricept Complexed with Acetylcholinesterase: Difference between revisions

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  <scene name='1eve/E2020_in_ache/3'>E2020-TcAChE</scene>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.