3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase
(see also AChE bivalent inhibitors (Part II))
Background
Uns quants inhibidors de colínesterases estan sent utilitzats per al tractament simptomàtic de la enfermetat d'Alzheimer o estan en tractaments clínics avançats. E2020, comercialitzat as Aricept, és un membre d'una família d'inhibidors de l'acetilcolínesterasa (AchE) basats en N-bencilpiperidine desenvolupats, sintetitzats y evaluats per la companyia Eisai al Japó. Aquests inhibidors van ser dissenyats utilitzant estudis de QSAR (relació estructura-función quantitativa) avans de la determinació de la estructura 3D de la AChE de Torpedo californica (1ea5). L'inhibidor posés una major eficàcia en models animals d'hipofunció colinèrgica i té una alta afinitat per AchE, unint-se tant a l'anguila elèctrica como a la AChE de ratolí a concentracions de nanomolar.
Results
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 .
Conclusions
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
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 Resources
For additional information, see: Alzheimer's Disease
