title: Transition States, analogues, and drug development.
abstract: Enzymes achieve their transition states by dynamic conformational searches on the femtosecond to picosecond time scale. Mimics of reactants at enzymatic transition states bind tightly to enzymes by stabilizing the conformation optimized through evolution for transition state formation. Instead of forming the transient transition state geometry, transition state analogues convert the short-lived transition state to a stable thermodynamic state. Enzymatic transition states are understood by combining kinetic isotope effects and computational chemistry. Analogues of the transition state can bind millions of times more tightly than substrates and show promise for drug development for several targets.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx New York 10461, United States. vern.schramm@einstein.yu.edu
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D015195:Drug Design; D004798:Enzymes / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019469:Indinavir / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular
chemical_list: D004798:Enzymes; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease