TARGETING A HOTSPOT IN CALCITONIN GENE RELATED PEPTIDE RECEPTOR; HOW TO PROCEED?

Article history Calcitonin Gene Related Peptide (CGRP) receptor has numerous implications on physiological processes in the body. Their effects range from vascular modulation to neurological disorders. Hence it's always been a spotlighted target for many researchers working on these disorders. Even though it has crossed almost two decades since the importance of the receptor has been reported, not even a single drug molecule has made it to the market. Targeting the receptor using small molecule antagonists have proved to be unfruitful because of the receptor being a heterodimeric protein and the surface of the protein- protein interaction is large. However, most of the ligands developed and documented for this receptor have ignored some aspects of Lipinski's rule of five especially with the molecular weight descriptor as small molecules are insufficiently fit inside the pocket leaving the key amino acids let loose. Even after compromising with several issues, hitting the 'Hotspot' proved to be easier said than done. Hence in this paper, we will study some aspects like how the receptor is formed and which protein-protein interactions result in the formation of CGRP as well as 'CGRP like' receptor using target identifying and bioinformatics' online/offline tools and put forth a brief study on the receptor & the 'Hotspots' using the crystal structure of the protein and validating it using docking software. These observations might help to design a drug candidate with increased affinity, potency along with time and money factors which are important for drug discovery process. Overall, a comprehensive but concise research note on how to design some potential CGRP antagonists can be drawn as outcome from the current communication.