Case Study 3: Class B GPCR

finding lead-like hits from a 30mer native peptide ligand

Another success story for Cresset's FieldScreen™ technology involves a really challenging project. A client was looking for leads for a class B peptide GPCR for which no small-molecule inhibitors were known. The only information available was based on the natural ligand, a 30mer peptide. No crystal structure of the target protein was available.

Experiment indicated that the backbone of the ligand was likely to remain in a defined conformation, and that certain regions of the native ligand comprising 6 to 14 residues were involved in binding to the receptor. Cresset worked closely with the client's modellers in examining the experimental mutagenesis data and developed several field templates describing regions of the native ligand which were thought to be crucial for binding.

These templates were used to search through a database of 1.5 million commercially-available compounds. A total of 200 compounds were selected from the search, and of these, 41 were purchased by the client. Of these, 12 showed good inhibition at 30μM, with 6 being better than 10μM. The hits had a molecular weight range from 360 to 500, and were all non-peptidic lead-like molecules.

In this project, Cresset was able to turn a 30mer native peptide ligand into a collection of active small molecule hits amenable to medicinal chemistry.