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been suggested that specificity of proteinases in general is due to rigidity in the binding pockets [6];
broad specificity results from the ability of the pockets to change shape in response to different ligand
side chains. However, renin is known to be inhibited by a wide variety of peptide analogs of different
length and sequence indicating either that the active site may be somewhat flexible or that the strength
of binding of a substrate does not determine the rate of subsequent turnover. This is emphasised by the
existence of substrates that act as competitive inhibitors, e.g., RIP of Haber and Burton [7], which has a
K i that is lower than the K m. Therefore hydrolysis of bound substrate appears to be more specific than
the binding step. This may be because only certain substrate sequences allow correct positioning of the
scissile bond for hydrolysis. Evidence for this effect was provided by comparison of 21 inhibitor
structures of endothiapepsin [8], where it was shown that for inhibitors with different sequences but with
the same transition state analog, the scissile bond analog can be disposed somewhat differently with
respect to the catalytic carboxyls in each case.
The availability of crystal structures of a number of renin inhibitors complexed with fungal aspartic
proteinases [8, 9] allowed new compounds to be designed and modeled by such techniques as computer
graphics, energy minimization, and molecular dynamics [10]. X-ray crystallographic analysis of aspartic
proteinase inhibitor complexes has made a significant contribution to rationalizing the activity data for
many of these compounds as well as understanding the catalytic mechanism of this class of proteinase.
II. Strategies for Design of Renin Inhibitors
Some of the parameters that have been varied in the search for therapeutically active renin inhibitors are
outlined below.
A. Elaboration of the Transition State Analog
There is no evidence that aspartic proteinase catalysis involves a covalently bound intermediate [11] and
major advances in the design of nonhydrolysable analogs have stemmed from attempts to mimic an
intermediate of the following form.
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