Irreversible inhibitors

Compounds that inhibit enzymes may either act reversibly, so that the inhibition gradually wears off as the inhibitor is metabolized, or irreversibly, causing chemical modification of the enzyme protein, so that the effect of the inhibitor is prolonged, and only diminishes gradually as the enzyme protein is catabolized and replaced (section 9.1.1).

It is important when designing drugs to know whether they act as reversible or irreversible inhibitors. An irreversible inhibitor may only need to be administered every few days; however, it is more difficult to adjust the dose of an irreversible inhibitor to match the patient's needs, because of the long duration of action. By contrast, it is easy to adjust the dose of a reversible inhibitor to produce the desired effect, but such a compound may have to be taken several times a day, depending on the rate at which it is metabolized and excreted from the body.

Irreversible inhibitors are chemical analogues of the substrate, and bind to the enzyme in the same way as does the substrate, then undergo part of the reaction sequence of the normal reaction. However, at some stage they form a covalent bond to a reactive group in the active site, resulting in inactivation of the enzyme. Such inhibitors are sometimes called mechanism-dependent inhibitors, or suicide inhibitors, because they cause the enzyme to commit suicide.

Experimentally, it is simple to distinguish between irreversible and reversible inhibitors; a reversible inhibitor can be removed from the enzyme (for example by dialysis), and this will restore activity. By contrast, an irreversible inhibitor, being covalently bound, cannot be removed by dialysis, and so activity cannot be restored.

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