Structure-function characterization of a key protein component of the endocannabinoid system, the human cannabinoid receptor 1 (CB1), is the central focus of this research proposal.
It aims to develop a fundamental understanding of the structural basis of CB1 function, with the ultimate translational goal of establishing a robust structure-based drug design (SBDD) program based on experimentally determined 3-dimensional structures. The endocannabinoid system is a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological processes, including nociception, inflammation, sleep, and drug addiction. As with other G protein coupled receptors, CB1 can exhibit preferential signaling events in response to different ligands. This functional selectivity offers the opportunity to discover new medications with improved pharmacological profiles, enhanced therapeutic properties and reduced side effects. The study will provide the structural basis for the design and development of functionally distinct CB1 selective compounds as useful pharmacological tools and/or leads for the future development of therapeutics. Several crystal structures will be solved to better understand molecular recognition, signaling, and to assist in the design of novel compounds that could then serve as prototypes for later generation leads and drug candidates. The study has three specific aims: (1) Design and synthesize covalent ligands representing key classes of cannabinergic ligands that have been shown to have distinct functional profiles, (2) Develop a better understanding of the CB1 orthosteric binding site by solving the 3D structure of several receptor-ligand complexes, and (3) Develop a better understanding of the CB1 active state by solving the structure of the CB1 signaling complex.
The study focuses on the cannabinoid receptor 1, which is an important component of the endocannabinoid system, a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological/pathophysiological processes, including nociception, inflammation, sleep, and drug addiction. Results from the proposed work should form the basis for the design of novel medications with improved pharmacological profiles and reduced side effects for the treatment of medical conditions such as addiction and pain management.
| Finlay, David B; Cawston, Erin E; Grimsey, Natasha L et al. (2017) G?s signalling of the CB1 receptor and the influence of receptor number. Br J Pharmacol 174:2545-2562 |
| Hua, Tian; Vemuri, Kiran; Nikas, Spyros P et al. (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547:468-471 |
| Hua, Tian; Vemuri, Kiran; Pu, Mengchen et al. (2016) Crystal Structure of the Human Cannabinoid Receptor CB1. Cell 167:750-762.e14 |
