Drug design toxicity mechanisms

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. 

Such a variety of mechanisms makes it difficult to point at molecular functions susceptible to produce toxic effects through bioactivation. However, some major toxo-phoric groups may be highlighted (Table 33.1). They may be implicated in acute or chronic toxicity. These patterns must be of particular concern in drug design. A number of recent papers on these matters have been published on how to avoid those toxic events in drug design. ... 

The subject of non-equilibrium situations such as pseudo-irreversible inhibition in drug design has been reviewed by Dr David Swinney, who concluded that first, in the absence of mechanism-based toxicity, drug mechanisms that create transitions to a non-equilibrium state will be more efficient second, in the presence of mechanism-based toxicity, biochemical mechanisms that maintain equilibrium to achieve a tolerable balance between efficacy and toxicity are desired. Non-equilibrium states, of course, include slow-off rate and irreversible inhibition. 

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