Classification of Inhibitors

The first major division of inhibitors is into two large groups of compounds irreversible and reversible inhibitors. Irreversible inhibitors are enzyme poisons, often chemically reactive compounds, which enter into chemical reactions with enz5nnes, forming irreversibly covalent bonds with the enzyme and reducing its activity to zero. An enzyme inactivated by an irreversible inhibitor caimot be reactivated by dialysis or a similar mild physical procedure. Many enzymes are poisoned by trace amounts of heavy metal ions this type of inhibition can be, in principle, reversed by dialysis against chelators such as EDTA or histidine. 

A much more important class of inhibitors for the study of enz mie kinetics is thatof reversible inhibitors. Reversible inhibitors usuallyformnoncovalentcomplexes with various enzyme forms and thus lower the amount of enz5mie available for participation in the normal reaction sequence. Reversible inhibitors can be removed by dialysis, and the cataljdic activity of enzyme restored completely. 

AH reversible inhibitors form dynamic complexes with the enz5mie that have different catal dic properties from those of the free enzyme. Reversible inhibitors are divided, according to their influence on the kinetic behavior and on kinetic parameters of the enzymatic reaction, into three major types (1) competitive, (2) noncompetitive, and (3) uncompetitive. 

It is important to note that the competitive inhibition wiU take place in enzyme reactions with one or more substrates or products, whereas the noncompetitive and uncompetitive inhibition wiU take place almost only in reactions with two or more substrates or products (Cleland, 1963 Dixon Webb, 1979 Fromm, 1979,1995). 

Further division of reversible inhibitors is made according to their influence on the form of rate equations thus, we can make a difference between the linear and a nonlinear inhibition. In Chapter 5, we shall describe the linear inhibition and in Chapter 6 the main forms of the nonlinear inhibitioa Thus, we could distinguish tfie various types of inhibition stiU further by referring to competitive inhibition as linear, hyperbolic, or paraboUc inhibition. Fven more complex forms are possible (Cleland, 1970). 

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The mechanisms of corrosion inhibition will be described separately for acid and neutral solutions, since there are considerable differences in mechanisms between these two media. Definitions and classifications of inhibitors are given in Section 17.2 and by Fischer. ... 

A much more useful classification of inhibitors can be made on the basis of the mechanisms by which they act. Competitive inhibitors combine, with the enzyme at the same site as the substrate does, thus blocking the first step in the sequence. Noncompetitive inhibitors combine with the enzyme at some other site to give a complex that can still combine with the substrate, but the resultant ternary complex is unreactive. Uncompetitive inhibition results when the inhibitor and substrate combine with enzyme forms as in the following mechanism. 

In addition to the classification of inhibitors according to their mechanisms of the action on oxidation, they can be classified into consumable and long-lived inhibitors. A consumable inhibitor is irreversibly consumed in its reactions with free radicals (R or RCV) or hydroperoxide. The stoichiometric coefficient of inhibition of such inhibitors is typically equal to one or two per inhibitory functional group. However, in some systems (for example RH 02 InH), an inhibitor can act cyclically so that, getting repeatedly regenerated, the... 

B. Example 2 CYP3A Classification of Inhibitors Evaluation of Substrate Independence... 

This approach can be easily reproduced with other CYP3A-sensitive substrates, such as buspirone, triazolam, and eplerenone, and yields quantitative examination of the relationship between these sensitive substrates and midazolam. This question was pursued in some depth by Ragueneau-Majlessi et al. (22) and showed that classification of inhibitors (five moderate and eight potent) was substrate independent in 74% to 83% of the instances. Exceptions pertained to buspirone and simvastatin that seemed to be systematically more sensitive than midazolam and saquinavir that appeared less sensitive (22). Furthermore, results of this analysis allow an extrapolation of the inhibitory effect of a compound from one probe to another avoiding a duplication of studies (i.e., effects of inhibitor on simvastatin calculated from its effect on midazolam). 

CYP3A substrates or CYP3A substrates with a narrow therapeutic range will need to be described in various sections of the labeling, as appropriate. Similar classifications of inhibitors of other CYP enzymes are also discussed in the guidance and the FDA Web site (10,12) and listed in Table 2. 

Modern classification of inhibitors as hard, soft and borderline inhibitors (11th International Corrosion Congress, V. 3, p. 55)... 

Patankar, S.J. and Jurs, P.C. (2003b) Classification of inhibitors of protein tyrosine phosphatase IB using molecular structure based descriptors. 

Classification of inhibitors of bovine carbonic anhydrase II according to the electronic spectral properties of the adducts with cobalt(ll) derivatives. ... 

A common classification of inhibitors is based on their effects on the electrochemical reactions involved in the corrosion process. In the framework of mixed potential theory (see Chapter 1.3, this volume), these effects are most conveniently visualized by -log j I diagrams, such as shown in Fig. 1. For a freely corroding metal, the corrosion potential Eq and the corrosion... 

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