Transition-state analog enzyme inhibitors

R. N. Lindquist (1975). The design of enzyme inhibitors Transition state analogs. In E. J. Ariens (Ed.). Drug Design, vol. 5. New York Academic Press, pp. 23-80. 

The transition state analog (TSA) approach1651 which has proved so successful in the design of enzyme inhibitors and catalytic antibodies lends itself nicely, at least in principle, to the molecular imprinting of polymers. Polymerization carried out in the presence of the TSA, or with the TSA covalently but readily reversibly bound to a monomer, produces a polymer with a number of embedded TSA molecules. If these can be removed under rea-... 

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... 

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... 

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. 

R. H. Abeles, Enzyme Inhibitors Ground State/ Transition-State Analogs , Drug, Dev. Res. 1987, 10, 221-234. 

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". 

Also a new family of inhibitors exemplified by SUAM 1221 65 [75] has been described in which a pyrrolidinylcarbonyl function at the PI site is the crucial entity for enzyme recognition, giving rise to the transition state analog of the enzyme-substrate interaction. 

The substrate specificities of both mammalian and yeast hexo-kinases have been extensively studied (76,77). Nevertheless, work in this area continues both in the search for isoenzyme specific inhibitors and in increasingly detailed investigations of the catalytic mechanism. Recently potential transition state analogs PI-(adenosine-5 )-P3-glucose-6 triphosphate (Ap -glucose) and P1-(adenosine-5 )-P4-glucose-6 triphosphate (Ap.-giucose) were tested as inhibitors of four hexokinase isoenzymes. However, they were found to exhibit less affinity for the enzyme than either of the natural substrates alone (78). 

Some boronic acid-based enzyme inhibitors undergo strong yet reversible covalent attachment to a nucleophile at the enzyme s active site, while others simply act as competitive inhibitors in their borate conjugate base form. Boronic acid-based inhibition of thrombin has been achieved <93MI109>, and that of P-lactamases has been particularly effective <95TL8399, 96M1688>. When compared to other covalent transition-state analog inhibitors of P-lactamases like phos-... 

Two specific enzyme-inhibitor mechanisms deserve special discnssion becanse they are the basis of action for several important drags. They are the transition-state analogs and the snicide snbstrates. 

R. Wolfenden (1976). Transition state analog inhibitors and enzyme catalysis. Annu. Rev. Biophys. Bioeng. 5 271-306. 

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