Computational Study and Subsequent Synthesis of Kavalactones as Potential CB1 Ligands
Johnson, Luke Norman
MetadataShow full item record
The endocannabinoid system is comprised of two known subtypes, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). The high sequence homology of CB1 and CB2 has limited the number of ligands that demonstrate selectivity for CB1 over CB2 or vice versa. Ligands targeted to the CB1 receptor have shown therapeutic potential towards a broad range of diseases including sleep disorders, diarrhea, neurodegenerative diseases, migraines, and seizures. As such it would be beneficial to develop CB1 selective ligands as potential therapeutics. The naturally occurring kavalactone yangonin has shown moderate binding affinity for CB1 however the functional activity of yangonin at CB1 is unknown nor its CB1/CB2 selectivity. Given this it would be beneficial to use computational methods such as ligand docking and molecular dynamics to provide more information about the protein-ligand interactions between CB1 and Yangonin. The work presented in this study highlights our initial ligand docking studies to identify an optimal binding pose within the binding pocket of CB1 and molecular dynamics simulations to understand protein-ligand interactions. Key results from this work showed that Yangonin may interact mainly with hydrophobic residues Phe102, Met103, Ile105, Gly166, Phe170, Phe379, Cys386, and Leu387 and forms a hydrogen bond with Ser383. These results have been applied to design a series of novel Yangonin analogues with potentially greater selectivity and affinity for CB1. Their chemical synthesis is also presented herein.