Tight binding inhibition

Many irreversible inhibitors and potent reversible compounds give IC50 50% binding sites. Such IC50 values, therefore, help in the qualitative 

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Slow, tight-binding inhibition occurs when slow-binding inhibition takes place at inhibitor concentrations comparable to that of the enzyme, in which case the previous two mechanisms can still apply. Comprehensive review articles on the subject of tight, slow, and slow, tight-binding inhibitors ate available in the literature (12,14). 

In this chapter we consider the situation where this assumption is no longer valid, because the affinity of the inhibitor for its target enzyme is so great that the value of K w approaches the total concentration of enzyme ( / T) in the assay system. This situation is referred to as tight binding inhibition, and it presents some unique challenges for quantitative assessment of inhibitor potency and for correct assessment of inhibitor SAR. 

Effects of Tight Binding Inhibition on Concentration-Response Data 179... 

EFFECTS OF TIGHT BINDING INHIBITION ON CONCENTRATION-RESPONSE DATA... 

The main issue with tight binding inhibition, from a medicinal chemistry perspective, is the limitations imposed by this behavior on following SAR. As the inhibitor affinity increases to the point where Arfpp is less than or equal to the enzyme con-... 

All these aspects of tight binding inhibition can potentially offer important advantages in terms of clinical efficacy, dosing interval, and patient safety (see Swinney, 2004, for an excellent review of some of the clinical advantages of tight binding inhibition and other nonclassical inhibition mechanisms). 

A (rapidly) reversible inhibitor will permit rapid and complete recovery of enzyme activity by dialysis. However, irreversible inhibitors are not removed by this procedure. Recovery from tight-binding inhibition is usually slow it is not uncommon for several dialysis bags containing enzyme to be prepared and for activity in each to be determined at various time points following the commencement of dialysis. The off-rate of these inhibitors is generally more rapid at higher temperatures. 

Morrison JR 1982. The slow-binding and slow, tight-binding inhibition of enzyme-catalysed reactions. Trends Biochem... 

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