Mechanism-based inhibitor design

QUINONE METHIDES AND AZA-QUINONE METHIDES AS LATENT ALKYLATING SPECIES IN THE DESIGN OF MECHANISM-BASED INHIBITORS OF SERINE PROTEASES AND p-LACTAMASES... 

The starting point for much of the work described in this article is the idea that quinone methides (QMs) are the electrophilic species that are generated from ortho-hydro-xybenzyl halides during the relatively selective modification of tryptophan residues in proteins. Therefore, a series of suicide substrates (a subtype of mechanism-based inhibitors) that produce quinone or quinonimine methides (QIMs) have been designed to inhibit enzymes. The concept of mechanism-based inhibitors was very appealing and has been widely applied. The present review will be focused on the inhibition of mammalian serine proteases and bacterial serine (3-lactamases by suicide inhibitors. These very different classes of enzymes have however an analogous step in their catalytic mechanism, the formation of an acyl-enzyme intermediate. Several studies have examined the possible use of quinone or quinonimine methides as the latent... 

Wakselman, M. Mazaleyrat, J.-P. Lin, R. C. Xie, J. Vigier, B. Vilain, A. C. Fesquet, S. Boggetto, N. Reboud-Ravaux, M. Design, synthesis and study of a selective cyclopeptidic mechanism-based inhibitor of human thrombin. In Peptides Chemistry, Structure... 

Dihydrofolate Reductase Free Energy Calculations for the Design of Mechanism-Based Inhibitors... 

More recently fluoromethylene deoxycytidines have been rationally designed by McCarthy et al. as bio-precursors of mechanism-based inhibitors of RDPR, after phosphorylation in vivo by the deoxycytidine kinase. Among these, tezacita-bine (MDL 101731) [92] has a high anti-proliferative activity and is currently in clinical phase III evaluation for the treatment of solid tumours [92],... 

Interactions with metabolic enzymes fluorinated amino acids are peptidomi-metic units or reactive entities used to design either reversible enzyme inhibitors (analogues of substrates) or irreversible enzyme inhibitors (mechanism-based inhibitors). 

When mechanism is understood, mechanism-based inhibitors such as transition state analogues and suicide inhibitors (Section 3.4) may also be designed. Recent determination of the crystal structure of a complex of penicillin G with a deacylation-defective mutant /3-lactamase from E. coli shows how such antibiotics are recognized and how they are destroyed (Strynadka et al., 1992). 

Suicide inhibitors, alternatively known as Kcat or irreversible mechanism based inhibitors (IMBIs), are irreversible inhibitors that are often analogues of the normal substrate of the enzyme. The inhibitor binds to the active site, where it is modified by the enzyme to produce a reactive group, which reacts irreversibly to form a stable inhibitor-enzyme complex. This subsequent reaction may or may not involve functional groups at the active site. This means that suicide inhibitors are likely to be specific in their action, since they can only be activated by a particular enzyme. This specificity means that drugs designed as suicide inhibitors could exhibit a lower degree of toxicity. 

Currently, efforts are underway to obtain more structural information on desaturases to address the mechanistic issues that have been raised through substrate-based studies. The need for more detailed 3-D active-site information is acute, particularly in the case of membrane-bound desaturases for which only hypothetical models currently are available. Design of mechanism-based inhibitors of medically relevant desaturases such as stearoyl CoA desaturase (SCD) (metabolic syndrome) (32), DesA3 (tuberculosis) (33), and dihydroceramide desaturase (apoptosis) (34, 35) also will be aided by new structural data. 

Groutas WC, Kuang R, Venkataraman R, Epp JB, Ruan S, Prakash O. Stmcture-based design of a general class of mechanism-based inhibitors of the serine proteinases employing a novel amino acid-derived heterocyclic scaffold. Biochemistry 1997 36 4739-4750. 

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