title: Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors.
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.
authors.affiliation: Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5YW, United Kingdom.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Gloster
authors.forename: Shirley
authors.initials: S
authors.lastname: Roberts
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perugino
authors.forename: Mosè
authors.initials: M
authors.lastname: Rossi
authors.forename: Marco
authors.initials: M
authors.lastname: Moracci
authors.forename: Narendra
authors.initials: N
authors.lastname: Panday
authors.forename: Miroslav
authors.initials: M
authors.lastname: Terinek
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasella
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
mesh_terms: D019843:Archaeal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D005947:Glucose / Q000031:analogs & derivatives / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D048229:Sulfolobus solfataricus / Q000737:chemistry / Q000201:enzymology*; D013816:Thermodynamics; D020124:Thermotoga maritima / Q000737:chemistry / Q000201:enzymology*; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D019843:Archaeal Proteins; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; C029899:imidazole; D001617:beta-Glucosidase; D005947:Glucose