Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4'-epimerase inhibitors:toward the development of novel therapies for African sleeping sickness

Durrant, Jacob D. and Urbaniak, Michael D. and Ferguson, Michael A. J. and McCammon, J. Andrew (2010) Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4'-epimerase inhibitors:toward the development of novel therapies for African sleeping sickness. Journal of Medicinal Chemistry, 53 (13). pp. 5025-5032. ISSN 1520-4804

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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 microM, 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.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Medicinal Chemistry
Additional Information:
ACS Author choice under CC-BY
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1313
Subjects:
ID Code:
66389
Deposited By:
Deposited On:
17 Sep 2013 08:07
Refereed?:
Yes
Published?:
Published
Last Modified:
30 Oct 2020 02:10