Patrick Gentry Email & Phone Number

Netherlands

Utrecht, Netherlands

Hillerød, Denmark

Copenhagen, Denmark

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 have tested 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 have been 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. As the ligands’ activity and selectivity have been confirmed, more traditional pathway-specific pharmacological assays have been used to begin determining the signaling profiles of the orphan GPCRs and the pharmacological characteristics of the ligands themselves.

Copenhagen, Denmark

Parkville, Victoria, Australia

As a research fellow at the Monash Institute of Pharmaceutical Sciences I explored molecular-level interactions of small molecule drugs with neuroreceptors. In particular my interests were with the M5 muscarinic acetylcholine receptor, a possible target for therapies seeking to curb drug addiction. A novel class of small molecules, allosteric modulators, interact with and effect the M5 receptor in a unique manner that we do not yet fully understand. Through the use of mutagenesis techniques, radioligand binding, and functional assays, I conducted an in-depth exploration of the allosteric binding sites of the M5 receptor. Additionally, I worked closely with the structural biology team to generate stabilized M5 receptor protein that resulted in the first reported X-ray crystal structure of the M5 muscarinic acetylcholine receptor.

Nashville, Tennessee, United States

My dissertation research focused on the discovery, synthesis, optimization, and characterization of novel subtype-selective M5 muscarinic acetylcholine receptor ligands. With the highly selective small molecules produced by this project we hope to expand and enhance the chemical tools available to probe the functional and therapeutic role of M5 within the CNS.

Nashville, Tennessee, United States

As a research assistant I engaged in high-throughput medicinal chemistry, conducting multi-dimensional iterative parallel syntheses of highly subtype-selective allosteric modulators for the muscarinic acetylcholine receptor subtypes 1, 4, and 5. I subsequently applied these techniques to the exploration of the structure-activity relationships of allosteric modulators for the metabotropic glutamate receptor subtype 4.

Doctor Of Philosophy (Ph.D.), Chemical And Physical Biology

Bachelor Of Science, Cum Laude, Chemistry