Principles of Enzyme-Inhibitor Design

The first principle of enzyme inhibitor design is Use aU the available information . This information can be biological, functional, structural, chemical, or theoretical. There is such an immense amount of biological information on thrombin that it cannot be surveyed here we focus on thrombin as a serine protease of the trypsin family and take fibrinogen to be its primary substrate. A convenient way to look at the information available is from the more general to the very specific. For thrombin, we may take four levels the general catalytic mechanism the particular substrate types processed the structure of the protein and, often forgotten, the flexibihty of the protein required to achieve this function. 

Enzymes are biological catalysts the active site exists to correctly position a substrate molecule so that functional groups on the enzyme may perform chemistry on it. All trypsin-like enzymes have a catalytic triad of aspartic acid 102, histidine 57, and serine 195 in which the serine Oy is activated so that it may attack a 

Protein-Ligand Interactions From Molecular Recognition to Drug Design. Edited by H.-J. Bohm and G. Schneider 

Copyright 2003 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30521-1 

There is perhaps more three-dimensional structural information available on thrombin than any other enzyme. We will study selected examples of the use of such information, indicating the relevant Protein Data Bank (http //www.rcsb.org/ pdb/) entries [labcj for those who wish to visualize the structures in 3-D. 

---

The transition state analog (TSA) approach1651 which has proved so successful in the design of enzyme inhibitors and catalytic antibodies lends itself nicely, at least in principle, to the molecular imprinting of polymers. Polymerization carried out in the presence of the TSA, or with the TSA covalently but readily reversibly bound to a monomer, produces a polymer with a number of embedded TSA molecules. If these can be removed under rea-... 

One way to increase selectivity and duration of action of enzyme inhibitors is to design a substrate with a latent electrophile, which becomes unmasked only after it reacts in the active site. This type of inhibition is referred to as suicide or mechanism-based inhibition (1-5) and is, in principle, extremely selective. 

---