title: Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates.
abstract: 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.
authors.affiliation: Department of Biophysics, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hudock
authors.forename: C E
authors.initials: CE
authors.lastname: Sanz-Rodríguez
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sarah
authors.initials: S
authors.lastname: Odeh
authors.forename: Thomas
authors.initials: T
authors.lastname: Kosztowski
authors.forename: Annette
authors.initials: A
authors.lastname: Leon-Rossell
authors.forename: J L
authors.initials: JL
authors.lastname: Concepción
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: 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
chemical_list: D004164:Diphosphonates; D006593:Hexokinase