Reversible Inhibitors
Robert A. Copeland Ph.D. · 2000
In this chapter the author describes the modes by which an inhibitor can bind to an enzyme molecule and thus render it inactive. Graphical methods are introduced for the diagnosis of the mode of inhibitor interaction with the enzyme on the basis of the effects of that inhibitor on the apparent values of the kinetic constants Km and Vmax. Having thus identified the inhibitor modality, the author describes methods for quantifying the inhibitor potency in terms of Ki, the dissociation constant for the enzyme–inhibitor complex. Also in this chapter, the author introduces some of the physicochemical determinants of enzyme–inhibitor interactions and shows how these could be systematically varied for the design of more potent inhibitors. Finally he introduces the concept of structure-based inhibitor design in which the crystal or NMR structure of the target enzyme is used to aid the design of new inhibitor molecules in an iterative process of enzyme–inhibitor structure determination, new inhibitor design and synthesis, and quantitation of new inhibitor potency.