netLibrary - eBook Summary Structure-based Drug Design by ...

Document
Page 124
predictable geometry. A series of peptides containing these types of constraints can be useful for
extrapolating the steric and electronic environment of a given binding site. This structural information
can be derived regardless of whether or not the constrained peptide binds to the target receptor. Since
peptides can be prepared rapidly, it is typical to establish a structure-activity relationship using them and
then at some later time transpose that information onto a nonpeptide lead molecule in an attempt to
improve its potency.
As part of an expansion upon the hypothesis that a C-terminal β turn was a structural prerequisite to highaffinity
antagonist binding, a novel series of constrained decapeptides was prepared [22–24]. These
peptides are of the sequence DArg 0-Arg 1-Pro 2-Hyp 3-Gly 4-Phe 5-Ser 6-DHype 7-Y 8-Arg 9, where Y is either
tetrahydroisoquinoline-3-carboxylic acid (Tic), or octahydroindole-2-carboxylic acid (Oic). DHype
denotes an organic ether of D-4-hydroxyproline in either the cis or trans geometric form. The C-terminal
portion of a representative member of this class of peptides was shown—first by empirical calculation
[22], then by NMR at 600 MHz—to adopt a β turn nearly unambiguously (figure 2) [25,26]. Moreover,
it was shown by calculation that the turn was adopted regardless of the nature of the ether group (alkyl,
aryl, etc.) or its geometry (cis or trans). Hence, a diverse series of these peptides was initially used as a
tool to probe the steric and electrostatic topology of an antagonist
Figure 2
Lowest 5 kcal mol -1 of the calculated overall potential energy surface for a model
peptide of Ser-DHype(trans propyl)-Oic-Arg. The contour interval is 0.5 Kcalmol -1
and the highest (outermost) and lowest contour energy values are labeled.
Superimposed on the contour plots are values for ψ i+1 and ψ i+2 from each of the
thirty structures generated from the NMR data corresponding to the tetrapeptide
Ser-DHype(trans propyl)-Oic-Arg.
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_124.html (1 of 2) [4/5/2004 4:57:43 PM]