Enzyme Study As a Source of Strategy in Drug Design

Abstract

This chapter presents the enzyme study as a source of strategy in drug design. The mechanism whereby less than one bound mole of inhibitor per mole of enzyme can in time bring about complete inactivation of an active site has great importance for the study of enzymes for drug design. The process is best explained by considering that, when a ligand is adsorbed at a control site or a receptor site, it produces a small conformational change after desorption. If the relaxation time of the macromolecule is slow, it will not completely return to the original state before a second molecule is adsorbed and an added increment in conformational distortion produced. This gradual change in activity can continue until all activity is destroyed. This means that in instances where this process can occur, the Michaelis constant K m or the inhibition constant K i are not really constant but time-dependent. If this type of time-dependent deactivation of a receptor occurs in the whole animal in a manner similar to that in vitro , then in vitro data will be applicable to in vivo work. If, on the other hand, the enzyme is more stabilized against such time-dependent deactivation by the constellations of macromolecules surrounding it in living tissue, then results obtained in vitro could be misleading.