Aricept Complexed with Acetylcholinesterase (Vietnamese)

3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase (see also AChE bivalent inhibitors (Part II))

Background

Những chất ức chế Enzim được sử dụng trong điều trị bệnh Alzheimer hoặc đang trong thử nghiệm lâm sàng. E2020, tên gọi trên thị trường là Aricept, là một thành viên trong một nhóm chất ức chế Enzim N-benzylpiperidine-based acetylcholinesterase (AChE) đã được nghiện cứu phát triển, tổng hợp và kiểm duyệt bởi công ty Eisai ở Nhật. Những chất ức chế này được thiết kế đựa trên nền tảng của nghiên cứu QSAR, và sau đó được làm sáng tỏ bằng cấu trúc 3D của AChE thuộc loài Torpedo californica. Chất ức chế này tác dụng rất đáng kể trên cuộc thử nghiệm ở động vật kém khả năng cholinergic và có ái lực nM đối với AChE ở lươn điện và chuột.

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) (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.

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