Mechanistic Insights into Mode of Action of a Potent Natural Antagonist of Orexin Receptor-1 by Means of High Throughput Screening and Molecular Dynamics Simulations

Abstract

Insomnia is one of the most common clinical problems being faced by people all over the world. It adversely affects the routine life of these patients giving rise to even other health issues like hypertension, diabetes, obesity, depression, heart attack, and stroke. Orexin receptor-1 (OX1R), a noteworthy drug target, when inhibited can promote sleepiness in people suffering from such conditions. OX1R is a G-protein coupled receptor which is conserved throughout the mammalian species and is located primarily in hypothalamus and locus coeruleus. The present study aims at identifying potent natural-origin inhibitors of OX1R capable of affecting the arousal and sleep pattern. In the present work, we have screened a large dataset of natural compounds against OX1R using high throughput screening and high precision docking approaches. Molecular dynamics simulations were carried out to study the dynamical behavior of the top scoring compound. We also provided mechanistic insights into the binding mode of action of this compound. The study provides evidence for consideration of this natural molecule as prospective lead in treatment of insomnia.