title: Rational design of transition-state analogues as potent enzyme inhibitors with therapeutic applications.
abstract: The structures of the transition states for a variety of enzyme-catalyzed ribosyl group transfer reactions, determined by computational evaluation of multiple tritium and heavy atom kinetic isotope effects on these enzymatic reactions, have been found to show a considerable variation in the extent of bond cleavage at the ribosyl anomeric carbon. The calculated transition-state structures have been used to guide the design of high-affinity transition-state analogue inhibitors for 5'-methylthioadenosine nucleosidases with potential as therapeutic agents.
authors.affiliation: Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York 14260-3000, USA.
authors.forename: Tina L
authors.initials: TL
authors.lastname: Amyes
authors.forename: John P
authors.initials: JP
authors.lastname: Richard
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008968:Molecular Conformation; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D009699:N-Glycosyl Hydrolases