Patrick Ryan Gentry
Peptides and Proteins
Jagtvej 160, 2100 København Ø
GPCRs are essential mediators of normal cell function and their malfunction is associated with many disease states. Despite this importance, 121 (35%) non-olfactory GPCRs are classified as “orphan receptors”, that is, their endogenous ligand is not known. A key challenge to the study of orphan receptors is the lack of tool compounds with which to probe the receptors’ signaling pathway(s), mechanisms of action, and/or (patho)physiological function. Moreover, discovery of such probe compounds is hindered by the fact that little is known about the signaling pathway(s) of most orphan GPCRs, complicating the process of screening ligands for these receptors.
In my research I am testing hypothesis-based libraries of putative ligands that have been tailor-made to link the orphan receptors to small molecules with a high probability of selectivity, affinity, and potency. These ‘smart’ libraries build on unique cheminformatics mining of over 144,000 GPCR ligands and virtual screening of pharmacophores based on all available GPCR crystal structures. All handpicked candidate ligands will be screened in unbiased in vitro assays, such as the Epic dynamic mass redistribution assay, to visualize the broadest possible range of G protein-dependent and -independent signaling outputs. Once the ligands’ activity and selectivity are confirmed, traditional pathway-specific pharmacological assays will be used to begin determining the signaling profiles of the orphan GPCRs.