6] Kinetics of slow and tight-binding inhibitors

Abstract

Publisher Summary The interest in both slow and tight-binding inhibitors has been increasing, mainly, owing to their importance as chemotherapeutic agents, herbicides, and transition state analogs (reaction intermediate analogs). Although the quantitative description of the effects of these inhibitors poses special problems, it is worth emphasizing that there is nothing intrinsically different between the classical inhibitors and the tight-binding inhibitors. Usually, the derivation of the kinetic equations for these nonclassical inhibitors is carried out in the following way: first, an inhibition mechanism is proposed; second, some simplifying assumptions are set up; and, third, the corresponding kinetic equations are deduced. On the other hand, when the kinetic constants of a new (slow and/or tight-binding) inhibitor are to be determined, the following procedure is used: one or two alternative inhibition mechanisms are considered; the corresponding kinetic equations are fitted to the experimental data; and, finally, the model giving the best fit is accepted as correct and the corresponding kinetic constants taken as the real values. There are two extensive reviews about this type of inhibition, both of which include the kinetic aspects: the review by Williams and Morrison of tight-binding inhibition and the review by Morrison and Walsh about slow binding inhibitors. Thus, the present chapter discusses the aspects that have received less attention as well as some new developments, concerning the kinetics of slow and tight-binding inhibitors. Thus, it discusses a more general kinetic mechanism, the validity of commonly used simplifying assumptions, a procedure to determine the inhibition constants, and some more recent models for the analysis of slow and tight-binding inhibition.