Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.

Stacey M SouthallJoydeep BanerjeeJason BrownKristina ButkovicAndrew D CansfieldJulie E CansfieldMiles S CongreveGabriella CsekeFrancesca DeflorianMartina Petrovic HunjadiAntun HutinecTrinadh Kumar InturiRenata RupcicGordon SaxtyStephen P Watson

Published in: ACS medicinal chemistry letters (2022)

The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 ( 3 ) and HTL0029882 ( 4 ), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.

Keyphrases

binding protein
high resolution
minimally invasive
genome wide
copy number
magnetic resonance
dna methylation
computed tomography
transcription factor
dna binding
genome wide identification
drug induced