1HBJ

X-ray Crystal structure of complex between Torpedo californica AChE and a reversible inhibitor, 4-Amino-5-fluoro-2-methyl-3-(3-trifluoroacetylbenzylthiomethyl)quinoline

1HBJ の概要

• エントリーDOI: 10.2210/pdb1hbj/pdb
• 関連するPDBエントリー: 1ACJ 1ACL 1AMN 1AX9 1CFJ 1DX6 1E3Q 1E66 1EA5 1EEA 1EVE 1FSS 1OCE 1QID 1QIE 1QIF 1QIG 1QIH 1QII 1QIJ 1QIK 1QIM 1QTI 1SOM 1VOT 1VXO 1VXR 2ACE 2ACK 2DFP 3ACE 4ACE
• 分子名称: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: hydrolase, serine hydrolase, cholinesterase, insecticide
• 由来する生物種: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62786.59

構造登録者

Greenblatt, H.M.,Kryger, G.,Lewis, T.L.,Doucet, C.,Viner, R.,Silman, I.,Sussman, J.L. (登録日: 2001-04-16, 公開日: 2001-09-25, 最終更新日: 2024-10-23)

主引用文献

Doucet-Personeni, C.,Bentley, P.D.,Fletcher, R.J.,Kinkaid, A.,Kryger, G.,Pirard, B.,Taylor, A.,Taylor, R.,Taylor, J.,Viner, R.,Silman, I.,Sussman, J.L.,Greenblatt, H.M.,Lewis, T.L.
A Structure-Based Design Approach to the Development of Novel, Reversible Ache Inhibitors
J.Med.Chem., 44:3203-, 2001

PubMed Abstract: Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone (1) were designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure of the apoenzyme, a molecular modeling study determined the favored attachment positions on the 4-aminoquinoline ring (position 3 and the 4-amino nitrogen) and the favored lengths of a polymethylene link between the two moieties (respectively 5-6 and 4-5 sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar range. Activity data for close analogues lacking some of the postulated key features showed that our predictions were correct. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27 was in good agreement with our model. The design strategy is therefore validated and can now be developed further.

PubMed: 11563919
DOI: 10.1021/JM010826R

実験手法

X-RAY DIFFRACTION (2.5 Å)