Using Computational and Neurobiological Methods to Characterise the Stimulant Properties of Novel Psychoactive Substances (NPS) at the Dopamine Transporter

Abstract

The Neurokinin-1 Receptor (NK1R) is a G-protein coupled receptor activated by small neuropeptides of the tachykinin family. Its main agonist, Substance P (SP), was described in 1931 and has since been associated with pain, depression, nausea, inflammation, and immune responses. Not surprisingly, NK1R was found to be active in the central and peripheral nervous systems, and in the immune system, as has been the focus of multiple drug development efforts. Aprepitant, an NK1R antagonist, is currently approved by the U.S. Food and Drug Administration for the treatment of chemotherapy-induced and post-operative nausea. It has also demonstrated antiviral activity in a non-human primate Simian immunodeficiency virus model, and immunomodulatory activity in cART naive and cART treated HIV infected individuals. In this study, we have leverage recently determined structures for NK1R bound to multiple antagonists to determine the main elements of inhibition by aprepitant, helping efforts to produce new antagonists that may be used in depression and immunomodulatory treatments. The structure produced by X-Ray crystallographic studies was adapted to represent the receptor as found in the human body, and a representative model of the neuronal plasma membrane was created to embed NK1R. Using molecular dynamics simulations, the atomic-level description of this complex was analyzed to find key interaction motifs between drug and receptor. The dynamical network analysis methodology was employed, and generalized correlation coefficients were calculated based on the movement of atoms in the system. Future studies will be made to compare the antagonist with the agonist binding patterns, and highlight possible development routes for synthetic agonists that recover SP's activity.