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

Citation:
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.
PDB ID: 1HBJDownload
MMDB ID: 17311
PDB Deposition Date: 2001/4/16
Updated in MMDB: 2001/11
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 1HBJ: dimeric; determined by author and by software (PQS)
Molecular Components in 1HBJ
Label Count Molecule
Proteins (2 molecules)
2
Acetylcholinesterase
Molecule annotation
Chemicals (10 molecules)
1
4
2
2
3
2
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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