Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity.

Abstract

Obesity and patient morbidity has become a health concern worldwide. Obesity is associated with over activity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis and insulin resistance. Hypothalamic cannabinoid-1 receptor (CB1R) inverse agonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity but displayed neuropsychiatric side effects. Hence, there is a need to develop therapeutics which employs blocking peripheral CB1 receptors and still achieve substantial weight loss. In view of the same, adipose tissue CB1 receptors are employed for this study since it is more specific in reducing visceral fat. Computer aided structure based virtual screening finds application to screen novel inhibitors and develop highly selective and potential drug. The rational drug design requires crystal structure for the CB1 receptor. However, the structure for the CB1 receptor is not available in its native form. Thus, we modelled the crystal structure using a lipid G-Protein coupled receptor (PDB: 3V2W, chain A) as template. Furthermore, we have screened a herbal ligand Quercetin [- 2- (3, 4-dihydroxyphenyl) - 3, 5, 7-trihydroxychromen-4-one] a flavonol present in Mimosa pudica based on its better pharmacokinetics and bioavailability profile. This ligand was selected as an ideal lead molecule. The docking of quercetin with CB1 receptor showed a binding energy of -6.56 Kcal/mol with 4 hydrogen bonds, in comparison to the known drug Rimonabant. This data finds application in proposing antagonism of CB1 receptor with Quercetin, for controlling obesity.