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

TY - JOUR

T1 - Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4 '-epimerase inhibitors

T2 - toward the development of novel therapies for African sleeping sickness

AU - Durrant, Jacob D.

AU - Urbaniak, Michael D.

AU - Ferguson, Michael A. J.

AU - McCammon, J. Andrew

PY - 2010/7/8

Y1 - 2010/7/8

N2 - 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.

AB - 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.

KW - RELAXED COMPLEX SCHEME

KW - CELL-FREE MEDIUM

KW - MOLECULAR-DYNAMICS

KW - DRUG-RESISTANCE

KW - BIOMOLECULAR SIMULATION

KW - ALLOSTERIC MODULATORS

KW - RECEPTOR FLEXIBILITY

KW - NATURAL-PRODUCTS

KW - DISCOVERY

KW - PROTEIN

U2 - 10.1021/jm100456a

DO - 10.1021/jm100456a

M3 - Article

C2 - 20527952

SN - 0022-2623

VL - 53

SP - 5025

EP - 5032

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -