Projects per year
Abstract
Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4'-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 mu M, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.
Original language | English |
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Pages (from-to) | 5025-5032 |
Number of pages | 8 |
Journal | Journal of Medicinal Chemistry |
Volume | 53 |
Issue number | 13 |
DOIs | |
Publication status | Published - 8 Jul 2010 |
Keywords
- RELAXED COMPLEX SCHEME
- CELL-FREE MEDIUM
- MOLECULAR-DYNAMICS
- DRUG-RESISTANCE
- BIOMOLECULAR SIMULATION
- ALLOSTERIC MODULATORS
- RECEPTOR FLEXIBILITY
- NATURAL-PRODUCTS
- DISCOVERY
- PROTEIN
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Dive into the research topics of 'Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4 '-epimerase inhibitors: toward the development of novel therapies for African sleeping sickness'. Together they form a unique fingerprint.Projects
- 1 Finished
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Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research
Ferguson, M. (Investigator) & Gilbert, I. (Investigator)
1/10/08 → 31/05/14
Project: Research