Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors.
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.
Gloster
Tracey M
TM
Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5YW, United Kingdom.
Roberts
Shirley
S
Perugino
Giuseppe
G
Rossi
Mosè
M
Moracci
Marco
M
Panday
Narendra
N
Terinek
Miroslav
M
Vasella
Andrea
A
Davies
Gideon J
GJ
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
D019843:Archaeal Proteins; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; C029899:imidazole; D001617:beta-Glucosidase; D005947:Glucose