The calcitonin gene-related peptide (CGRP) is a 37-residue peptide wit
h pronounced physiological activities, making it an interesting lead f
or drug development, In our previous work, we designed constrained ana
logues of the peptide. The biological activities of these proved that
the disulfide bridges created favoured the active conformations of the
peptide. Here we report the molecular modelling of the conformation o
f domains involved in receptor activation. Our approach was to create
sets of possible conformations for three differently constrained bioac
tive regions by a random search of conformational space and molecular
modelling. The conformations were compared, and those allowed for all
derivatives were considered relevant for receptor activation. This app
roach resulted in one favoured group of conformations characterized by
an inverse gamma-turn followed by a gamma-turn, defining the conforma
tion of the tripeptide region with a similar sequence in all active an
alogues. The models may also be used for the design of peptide and non
-peptide analogues of CGRP.