Modelling constrained calcitonin gene-related peptide analogues

The calcitonin gene-related peptide (CGRP) is a 37-residue peptide with pronounced physiological activities, making it an interesting lead for drug development. In our previous work, we designed constrained analogues 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 of domains involved in receptor activation. Our approach was to create sets of possible conformations for three differently constrained bioactive 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 approach resulted in one favoured group of conformations characterized by an inverse gamma-turn followed by a gamma-turn, defining the conformation of the tripeptide region with a similar sequence in all active analogues. The models may also be used for the design of peptide and non-peptide analogues of CGRP.