Transition-State Affinity as a Basis for the Design of Enzyme Inhibitors

  • Richard Wolfenden


To bring about the large rates of reaction which occur in the presence of enzymes, the interaction between reacting substrates and enzymes must be strong and intimate. The fact that substrates form complexes with enzymes has been known since the time of Henri(1) and Michaelis and Mentent(2) and has been exploited in the design of inhibitors that resemble substrates. Enzyme—substrate affinity is far surpassed by the affinity which is developed transiently during catalysis, as was recognized by Paulingt(3) before much was known about enzyme mechanisms. This enhanced affinity can be exploited to produce more effective inhibitors, designed to resemble the substrate during its transformation to form products.(4–8) These inhibitors, usually designated “transition-state analogs,” (4) are bound very much more tightly than substrates. As of mid-1975, some 60 possible examples were known, and several potential transition-state analogs had also been found in nature.t(9,10)


Transition State Adenosine Deaminase Triosephosphate Isomerase Uncatalyzed Reaction Bovine Pancreatic Trypsin Inhibitor 
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Copyright information

© Springer Science+Business Media New York 1978

Authors and Affiliations

  • Richard Wolfenden
    • 1
  1. 1.Department of BiochemistryUniversity of North CarolinaChapel HillUSA

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