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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

(1994) JOURNAL OF MEDICINAL CHEMISTRY. 37(21). p.3605-3613
Author
Organization
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.
Keywords
BRUCEI-BRUCEI, GLYCOLYTIC-ENZYMES, PURINE, METABOLISM, RESOLUTION, PHOSPHATE

Citation

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Chicago
Verlinde, CLMJ, M Callens, Serge Van Calenbergh, Arthur Van Aerschot, Piet Herdewijn, V Hannaert, PAM Michels, FR Opperdoes, and WGJ Hol. 1994. “Selective-inhibition of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase by Protein Structure-based Design : Toward New Drugs for the Treatment of Sleeping Sickness.” Journal of Medicinal Chemistry 37 (21): 3605–3613.
APA
Verlinde, C., Callens, M., Van Calenbergh, S., Van Aerschot, A., Herdewijn, P., Hannaert, V., Michels, P., et al. (1994). Selective-inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design : toward new drugs for the treatment of sleeping sickness. JOURNAL OF MEDICINAL CHEMISTRY, 37(21), 3605–3613.
Vancouver
1.
Verlinde C, Callens M, Van Calenbergh S, Van Aerschot A, Herdewijn P, Hannaert V, et al. Selective-inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design : toward new drugs for the treatment of sleeping sickness. JOURNAL OF MEDICINAL CHEMISTRY. 1994;37(21):3605–13.
MLA
Verlinde, CLMJ, M Callens, Serge Van Calenbergh, et al. “Selective-inhibition of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase by Protein Structure-based Design : Toward New Drugs for the Treatment of Sleeping Sickness.” JOURNAL OF MEDICINAL CHEMISTRY 37.21 (1994): 3605–3613. Print.
@article{199754,
  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.},
  author       = {Verlinde, CLMJ and Callens, M and Van Calenbergh, Serge and Van Aerschot, Arthur and Herdewijn, Piet and Hannaert, V and Michels, PAM and Opperdoes, FR and Hol, WGJ},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {BRUCEI-BRUCEI,GLYCOLYTIC-ENZYMES,PURINE,METABOLISM,RESOLUTION,PHOSPHATE},
  language     = {eng},
  number       = {21},
  pages        = {3605--3613},
  title        = {Selective-inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design : toward new drugs for the treatment of sleeping sickness},
  volume       = {37},
  year         = {1994},
}