The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase a drug target for African sleeping sickness

Aaron J Friedman, Jacob D Durrant, Levi C T Pierce, Thomas J McCorvie, David J Timson, J Andrew McCammon

Research output: Contribution to journalArticle

12 Citations (Scopus)
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Abstract

During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10 000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose synthesis pathway is one potential therapeutic target. Although galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4'-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and is therefore of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.
Original languageEnglish
Pages (from-to)173-81
Number of pages9
JournalChemical Biology & Drug Design
Volume80
Issue number2
DOIs
Publication statusPublished - Aug 2012

Fingerprint

Uridine Diphosphate Galactose
African Trypanosomiasis
Trypanosoma brucei brucei
Uridine Diphosphate Sugars
Molecular Dynamics Simulation
Galactose
Molecular dynamics
UDPglucose 4-Epimerase
Trypanocidal Agents
Pharmaceutical Preparations
Uridine Diphosphate Glucose
Drug therapy
Protein Conformation
Africa South of the Sahara
Chirality
Poisons
Protein Transport
Drug Discovery
Conformations
Parasites

Cite this

Friedman, Aaron J ; Durrant, Jacob D ; Pierce, Levi C T ; McCorvie, Thomas J ; Timson, David J ; McCammon, J Andrew. / The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase a drug target for African sleeping sickness. In: Chemical Biology & Drug Design. 2012 ; Vol. 80, No. 2. pp. 173-81.
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The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase a drug target for African sleeping sickness. / Friedman, Aaron J; Durrant, Jacob D; Pierce, Levi C T; McCorvie, Thomas J; Timson, David J; McCammon, J Andrew.

In: Chemical Biology & Drug Design, Vol. 80, No. 2, 08.2012, p. 173-81.

Research output: Contribution to journalArticle

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