Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors

Tracey M. Gloster, Shirley Roberts, Giuseppe Perugino, Mose Rossi, Marco Moracci, Narendra Panday, Miroslav Terinek, Andrea Vasella, Gideon J. Davies

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.

Original languageEnglish
Pages (from-to)11879-11884
Number of pages6
JournalBiochemistry
Volume45
Issue number39
DOIs
Publication statusPublished - 3 Oct 2006

Keywords

  • TRANSITION-STATE
  • SUBSTRATE DISTORTION
  • MOLECULAR GRAPHICS
  • BETA-GLUCOSIDASES
  • BINDING
  • GLUCOHYDROLASE
  • DISSECTION
  • DEPENDENCE
  • SNAPSHOTS
  • COMPLEX

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