Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4'-epimerase inhibitors: toward the development of novel therapies for African sleeping sickness.
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.
Durrant
Jacob D
JD
Biomedical Sciences Program, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, California 92093-0365, USA. jdurrant@ucsd.edu
Urbaniak
Michael D
MD
Ferguson
Michael A J
MA
McCammon
J Andrew
JA
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D014534:UDPglucose 4-Epimerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D014534:UDPglucose 4-Epimerase