Enzyme inhibition as a source of new drugs

Abstract

The significance of enzymes as targets of drug action is discussed. New approaches to the rational design of enzyme inhibitors are characterized by a pronounced shift of emphasis toward the targets of drug action, as the structure and function of an increasing number of enzymes are described in great detail. The most promising of the recently developed approaches is the design of mechanism‐based enzyme inhibitors and, in particular, suicide inactivators. These require enzymic activation of “latent” functional groups to chemically reactive species. The various functionalities currently encountered are reviewed, grouped into chemical categories. The various aspects of the selectivity and the specificity of mechanism‐based enzyme inhibitors, as well as the stability of drug‐enzyme complexes, are discussed in detail. Reversible covalent bond formation is demonstrated by the recovery of thymidylate synthetase activity after inactivation by various 5‐substituted pyrimidine analogs, using purified bacterial enzyme preparations or intact mammalian cells. The fragmentation and secondary reactions of the inhibitor within the complex are described using typical examples of the action of penicillin on its targets and clavulanate on /3‐lactamase, respectively. The perspectives of enzyme inhibitory drug development are discussed, and some of the many areas currently undergoing rapid exploration are mentioned. It is concluded that the rational design of enzyme inhibitors will play an ever‐increasing and significant role in new drug discovery and development.

The organic chemistry of mechanism‐based enzyme inhibition: A chemical approach to drug design

“…This was exemplified in (1).25 IS(az)/EL(ha), RE(si)/SU(SN2); B.1.c. The inhibition of cystathionine ysynthetase and methionine y-lyase by 2-amino-4-chloro-5(nitrophen-ylsulfiy1)pentanoic acid was reversed upon treatment with thiols.= The key step in the inhibition mechanism is a [2,3]-sigmatropic rearrangement as in(13).…”