Transition state analogs binding

Transition-State Analogs Bind Very Tightly to the Aetive Site... 

Interestingly, although many transition state analogs bind noncovalently to the target enzyme s active site via a one-step kinetic mechanism (Scheme la) and would therefore be expected to exhibit no time-dependent properties of inhibition, inhibitors with Kj values of < 10 10 M (like coformy-cin) usually have a slow onset of inhibition kobserved < 10 2 s 1 (i.e., an approach to equilibrium inhibition of > 1 min).161 This is merely an assay artifact due to... 

Baca, M., Scanlan, T. S., Stephenson, R. C., and Wells, J. A. (1997). Phage display of a catalytic antibody to optimize affinity for transition-state analog binding. Proc. Natl. Acad. Sci. USA, 94(19), 10063-10068. 

It should be noted that transition-state analogs are only approximations of the transition state itself and will never bind as tightly as would be expected for the true transition state. These analogs are, after all, stable molecules and cannot be expected to resemble a true transition state too closely. 

TRANSITION-STATE ANALOGS are stable molecules that are designed to look more like the transition state than like the substrate or product. Transition-state analogs usually bind to the enzyme they re designed to inhibit much more tightly (by 1000-fold or more) than the substrate does. 

Concept A new approach to the rational design of enzyme inhibitors has emerged in the last ten to fifteen years that incorporates a substrate (or transition state) analog "core" molecule with additional binding determinants spanning beyond the immediate... 

Bartlett has derived a method181 for proving that a putative transition state analog exerts its inhibitory power from successfully mimicking the transition state. If a series of structurally-related inhibitors (all containing the identical core chemical structure meant to simulate the transition state) bind to the target enzyme with log (fQ) values that linearly correlate (slope = 1) with the log (KMlkcai) values of the same series of structurally-related substrates, then... 

This analysis reveals that enzymes bind the transition state more tightly than the ground state by a factor approximately equal to the rate of acceleration (ie, Kjs/Ks kuncaJkcat)- This method has been used to show, for example, that the peptide phos-phonate inhibitors of carboxypeptidase A are true transition state analogs. 

M. M. Mader, P. A. Bartlett, Binding Energy and Catalysis The Implications for Transition-State Analogs and Catalytic Antibodies , Chem. Rev. 1997, 97,1281-1301. 

In our context, an important class of reversible inhibitors are the transition state analogs [18], which are stable compounds designed to mimic the structure of an intermediate in the path of substrate s transformation by the enzyme. Such analogs are based in Pauling s postulate [19], which states that "an enzyme recognises and binds more tightly to the transition state than to the ground state of the substrate". 

Inhibition of enzymatic reactions by transition state analogs has been an extremely important approach for drug design [20], the principle underlying this is that "nature has developed enzymes for binding efficiently to the transition states of the reactions they catalyse". 

Tian, G., Ghanekar, S.V., Aharony, D., et al. (2003) The mechanism of y-secretase. Multiple inhibitor binding sites for transition state analog and small molecule inhibitors. J. Biol. Chem., 278, 28968-28975. 

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