Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates.
Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.
Hudock
Michael P
MP
Department of Biophysics, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA.
Sanz-Rodríguez
C E
CE
Song
Yongcheng
Y
Chan
Julian M W
JM
Zhang
Yonghui
Y
Odeh
Sarah
S
Kosztowski
Thomas
T
Leon-Rossell
Annette
A
Concepción
J L
JL
Yardley
Vanessa
V
Croft
Simon L
SL
Urbina
Julio A
JA
Oldfield
Eric
E
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
D004164:Diphosphonates; D006593:Hexokinase