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residues that have been the main focus of attention hitherto. A key requirement now is to identify those
residues that provide the majority of the binding energy and to differentiate these from others whose
main role is to stabilize the binding residues in the active conformation.
VII. Mimicking The Pharmacophore
Significant progress has been made over the past few years in the field of peptide mimetics, although the
most successful examples are those where a small peptide ligand or a linear segment of a larger protein
has been the target [72–74]. An alternative approach to de novo design is to optimize a lead compound
obtained by screening chemical libraries on the basis of a knowledge of the conformation of the
polypeptide ligand, as in the case of the endothelin receptor antagonist SB 209670 [75].
The task of mimicking a pharmacophore is simplified where the contributing residues are contiguous in
the amino acid sequence. This is not the case in the anthopleurins, with residues from at least four
different regions of the sequence contributing to affinity. In charybdotoxin the essential residues come
from two or three regions of the sequence, depending on which potassium channel is considered, while
in growth hormone, binding site I is comprised of residues from three different regions of the protein
and site II from two regions. Mimicking the pharmacophore of the anthopleurins therefore represents a
task at least as challenging as those presented by these two examples. Strategies for achieving this goal
include de novo design, conformationally directed data base searching and screening chemical libraries
(synthetic and naturally occurring) for leads, which could then be optimized on the basis of our
knowledge of the structure. Our approach is based on the first two of these.
Initial attempts to mimic the pharmacophore of AP-A were based on linear and disulfide-cyclized
versions of the Arg14-containing loop [76]. At that time, our level of understanding of the
pharmacophore was inadequate and it is clear in retrospect that not enough of the key elements were
present. Nevertheless, conformational analysis of these peptides by NMR was useful in showing that
they retained several elements of local structure observed in the corresponding region of the native
protein, thereby emphasizing the independence of this loop from the rest of the structure in solution.
VIII. Conclusions
In this chapter I have attempted to summarize the current state of our understanding of the structure and
structure-function relationships of the type 1 sea
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