Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates

Michael P. Hudock, C. E. Sanz-Rodríguez, Yongcheng Song, Julian M.W. Chan, Yonghui Zhang, Sarah Odeh, Thomas Kosztowski, Annette Leon-Rossell, J. L. Concepción, Vanessa Yardley, Simon L. Croft, Julio A. Urbina, Eric Oldfield

Research output: Contribution to journalArticlepeer-review


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 IC50 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 IC50 values for 17 active compounds were predicted with an average error of 2.4 × by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 μM IC50 versus the clinically relevant intracellular amastigote form of T. cruzi, but only a ∼1-2 μM IC50 versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 12 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates'. Together they form a unique fingerprint.

Cite this