Protein-ligand interaction studies and identification of new drug-like hits as cannabinoid receptor modulators
Date of Award
Ph.D. in Pharmaceutical Sciences
Robert J. Doerksen
Steven R. Davis
Christopher R. McCurdy
The cannabinoid receptors (CB1 and CB2) belong to the family of class A GPCRs. The CB1 receptor is predominately found in the central nervous system and regulates various neuromodulatory and physiological processes while CB2 receptors are found in peripheral tissues, particularly in the immune system tissues. This dissertation reports several projects including: (1) an examination of the putative binding modes of Cannabis-derived ligands with CB1 and CB2 receptors, (2) the identification of novel CB1 inverse agonists, and (3) the identification of allosteric site(s) in the CB2 receptor and screening of new CB2 allosteric modulators (AMs).
Chapter 1 describes background information on cannabinoids and the endocannabinoid system. Chapter 2 focuses on the structure-activity relationships of Cannabis-derived ligands with CB1 and CB2 receptors. These compounds are known to exhibit nanomolar to micromolar affinities against the CB1 and CB2 receptors; however, little-to-no information is available about how they interact with the receptors at the molecular level. To understand the putative binding interactions of these ligands with the CB receptors, molecular docking and binding free-energy calculations were performed. The modeling results agree well with the experimental results and delineate key residues of CB1 and CB2 receptors that are engaged in H-bonding, aromatic stacking, and hydrophobic interactions with the ligand. Chapter 3 focuses on the identification of new CB1 inverse agonists using protein structure-based virtual screening. These compounds exhibited nanomolar to micromolar binding affinities against the CB1 receptor and antagonized basal GTPγS functional activity consistent with inverse agonist behavior. These compounds represent novel scaffolds that could be used to develop new CB1 inverse agonists with fewer or null psychiatric side effects compared to rimonabant. Chapter 4 focuses on the identification and characterization of CB2 allosteric site(s). Using known CB2 negative AMs, the binding energy of representative complexes after molecular dynamics studies validated the binding poses of AMs. Virtual screening revealed seven potential AMs and they have been submitted for in vitro testing. The results from this study could lead to the discovery of more effective and selective CB2 AMs. Finally, Chapter 5 includes the summary and conclusions of the research presented in this dissertation.
Pandey, Pankaj, "Protein-ligand interaction studies and identification of new drug-like hits as cannabinoid receptor modulators" (2015). Electronic Theses and Dissertations. 1465.