Design of Enzyme Inhibitors

Abstract

Mechanistic insight and structural information provide the starting points for two contrasting approaches to the design of enzyme inhibitors. Phosphorus-containing peptides are inhibitors of the zinc and aspartic peptidases that mimic key geometric and electronic characteristics of the transition states of these enzymes. The design of compounds to mimic high-energy structures along the reaction path is also an effective strategy for inhibition of two enzymes of the shikimic acid pathway, EPSP synthase and chorismate mutase. For all of these inhibitors, the structural information available from crystallography has been used to interpret their binding behavior, if not for their initial design. Situations in which structural information does play a role in inhibitor design can be divided into three categories, depending on the kind of information available; examples of two of these are presented, along with some computational tools to facilitate the design process. Macrocyclic, constrained inhibitors of thermolysin were designed from the structures of the enzyme complexes of the acyclic transition state analogs, and cyclic hexapeptide mimics of the α-amylase inhibitor tendamistat were designed from the structure of this 74-residue protein. In this connection, the utility of 3-D structural databases and search tools like CAVEAT has stimulated the development of TRIAD and ILIAD, two large databases of computed, minimized structures.