Substrate-based design

The pseudodipeptide amides represented a major advance in the substrate-based design of FTIs. They removed the metabolic liability of the prodrug, were cell active, and were considerably simpler chemically. However, the majority of pseudodipeptide amides were not potent enough and too cytotoxic to demonstrate activity in cell culture. Although the potency issue was perceived as solvable, the dark cloud of nonspecific cytotoxicity hovered over this particular class of compounds like an unwelcome visitor. Changes to the molecule which virtually destroyed FTase activity had no effect on the level of cytotoxicity, indicating that the observed toxicity was unlikely to be mechanism related. 

Type I Peptide backbone mimetics Substrate-based design Pseudopeptides... 

R 60 C.J. Dinsmore and I.M. Bell, Inhibitors of Farnesyltransferase and Ger-anylgeranyltransferase-I for Antitumor Therapy Substrate-Based Design, Conformational Constraint and Biological Activity , p. 1075... 

DESIGN AND SAR OF PEPTIDE DEFORMYLASE INHIBITORS Early Substrate-based Inhibitors... 

Scheme 1 is a gross over-simplification for almost any enzyme-catalyzed reaction of a specific substrate, based as it is on a one-step reaction with a single, rate-determining transition state but it is appropriate for many, if not most reactions catalyzed by simple enzyme mimics. Most important for present purposes, it emphasises the most important properties of enzyme reactions which the design of mimics, or artificial enzymes, must address, namely ... 

Classification trees are used to predict membership of cases or objects in the classes of a categorical dependent variable from their measurements on one or more predictor variables. Lewis et al. (334) used the concept of classification trees to design a decision tree for human P450 substrates. The intention was to predict which CYP isozyme will interact with which substrates, based on physicochemical parameters. The resulting classifiers are the volume, the... 

While the interaction of the substrate (and the inhibitor) with the catalytic zinc is the most important interaction, the remainder of the substrate (inhibitor) also forms hydrogen bonds with residues from the top strand of the 3 sheet and the loop region posterior to the Met-tum. These interactions with the substrate in the binding pockets of the MMPs are the prime targets for engineering specific MMP inhibitors. An in-depth understanding of the differences of the properties of these pockets in the different MMPs and the interactions of specific residues within these pockets is essential for structure-based design of inhibitors. 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

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