Mechanism-based inhibitors drug design

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. 

T. 1. Kalman, Ed., Drug Action and Design Mechanism-Based Enzyme Inhibitors. Elsevier North-Holland, New York, 1979. 

Kalman Tl, ed. Drug Action Design—Mechanism-Based Enzyme Inhibitors. New York Elsevier Science, 1979. 

In the real world, no chemist will be allowed to ignore mechanistic factors for long. Actives or hits shown to be irreversible will often be deprioritized or dropped, while enzyme inhibitors proving to be non-competitive or uncompetitive might even find additional support on that basis. Hits that may be allosteric receptor binders will require a lot of work in biochemistry and some specialized expertise. Attempts to use structure-based drug design on uncompetitive inhibitors which, you ll recall, uniquely bind to the enzyme-substrate complex, will be futile if crystallization is carried out in the absence of substrate because it s been assumed that the inhibitor is competitive instead. Mechanism matters. 

Richard B. Silverman, Structure-Based and Mechanism-Based Enzyme Inhibitor Drug Design and Drug Action, in Bioorg. Med. Chem., 4 (9), Pergamon, Oxford, UK, 1996. 

Gleeson MP, IH Hillier, NA Burton (2004) Theoretical analysis of peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase Insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design. Organic Biomolecular Chemistry 2 (16) 2275-2280... 

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