Transition-state analog 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. 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

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... 

Because a stable transition state analog can only approximate the actual transition state in terms of bond lengths, angles, partial charges, etc., inhibitors using this approach have usually fallen many orders of magnitude short of their theoretical maxi-... 

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... 

Figure 4. A diagnostic test for proving that an inhibitor is a true transition state analog (data points are representative only).

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. 

Vanadium is beneficial and possibly essential for humans. It is certainly essential for a number of organisms. Vanadate (oxidation state V) and its derivatives are phosphate analogues, showing both ground state and transition state analogy (both structural and electronic) with phosphorus compounds. The analogy of five-coordinate vanadium compounds with the transition state of phosphate ester hydrolysis is well documented, and explains why so many vanadium compounds are potent inhibitors of phosphatases, ribonucleases and ATPases. 

---