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Selective inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design: toward new drugs for the treatment of sleeping sickness.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1994 Oct 14; Vol. 37 (21), pp. 3605-13. - Publication Year :
- 1994
-
Abstract
- Within the framework of a project aimed at rational design of drugs against diseases caused by trypanosomes and related hemoflagellate parasites, selective inhibitors of trypanosomal glycolysis were designed, synthesized, and tested. The design was based upon the crystallographically determined structures of the NAD:glyceraldehyde-3-phosphate dehydrogenase complexes of humans and Trypanosoma brucei, the causative agent of sleeping sickness. After one design cycle, using the adenosine part of the NAD cofactor as a lead, the following encouraging results were obtained: (1) a 2-methyl substitution, targeted at a small pocket near Val 36, improves inhibition of the parasite enzyme 12.5-fold; (2) an 8-(thien-2-yl) substitution, aimed at Leu 112 of the parasite enzyme, where the equivalent residue in the mammalian enzyme is Val 100, results in a 167-fold better inhibition of the trypanosomal enzyme, while the inhibition of the human enzyme is improved only 13-fold; (3) exploitation of a "selectivity cleft" created by a unique backbone conformation in the trypanosomal enzyme near the adenosine ribose yields a considerable improvement in selectivity: 2'-deoxy-2'-(3-methoxybenzamido)adenosine inhibits the human enzyme only marginally but enhances inhibition of the parasite enzyme 45-fold when compared with adenosine. The designed inhibitors are not only better inhibitors of T. brucei GAPDH but also of the enzyme from Leishmania mexicana.
- Subjects :
- Adenosine chemistry
Adenosine pharmacology
Animals
Binding Sites
Deoxyadenosines pharmacology
Humans
Hydrogen Bonding
Leishmania mexicana enzymology
Molecular Structure
NAD chemistry
NAD metabolism
Protein Conformation
Structure-Activity Relationship
Deoxyadenosines chemical synthesis
Drug Design
Glyceraldehyde-3-Phosphate Dehydrogenases antagonists & inhibitors
Glyceraldehyde-3-Phosphate Dehydrogenases chemistry
Trypanosoma brucei brucei enzymology
Trypanosomiasis, African drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 37
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 7932587
- Full Text :
- https://doi.org/10.1021/jm00047a017