Prediction of essential binding domains for the endocannabinoid N-arachidonoylethanolamine (AEA) in the brain cannabinoid CB1 receptor.

Joong-Youn Shim,Alexandre G De Brevern

doi:10.1371/journal.pone.0229879

Joong-Youn Shim, Alexandre G De Brevern

Open Access

https://doi.org/10.1371/journal.pone.0229879

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Journal: PloS one	Publication Date: Jun 28, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Dalton State College, Physical Sciences (United States)

Abstract

Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa (marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics pharmacological effects of endocannabinoids (eCBs) like N-arachidonylethanolamide (AEA). Due to its flexible nature of AEA structure with more than 15 rotatable bonds, establishing its binding mode to the CB1 receptor is elusive. The aim of the present study was to explore possible binding conformations of AEA within the binding pocket of the CB1 receptor confirmed in the recently available X-ray crystal structures of the CB1 receptor and predict essential AEA binding domains. We performed long time molecular dynamics (MD) simulations of plausible AEA docking poses until its receptor binding interactions became optimally established. Our simulation results revealed that AEA favors to bind to the hydrophobic channel (HC) of the CB1 receptor, suggesting that HC holds essential significance in AEA binding to the CB1 receptor. Our results also suggest that the Helix 2 (H2)/H3 region of the CB1 receptor is an AEA binding subsite privileged over the H7 region.

Highlights

Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa, interacts with the brain cannabinoid (CB1) receptor and elicits a wide range of neurological, psychological and biological effects [1]
Toward understanding molecular mechanisms of marijuana action, these X-ray crystal structures have shed light on how the ligand activates the receptor upon binding at the molecular level. It is seen in the X-ray crystal structure of the classical cannabinoid full agonist AM11542-bound CB1 receptor [6] that the dimethyl heptyl (DMH) tail of the ligand binds the hydrophobic channel (HC), disrupting the toggle switch of Phe200/Trp356 a pair of key aromatic residues
Our results suggest that the Helix 2 (H2)/H3 region of the CB1 receptor is an AEA binding subsite privileged over the H7 region

Summary

Introduction

Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa (marijuana), interacts with the brain cannabinoid (CB1) receptor and elicits a wide range of neurological, psychological and biological effects [1]. Determined X-ray crystal structures of the CB1 receptor in complex with various ligands [4,5,6,7] have revealed the detailed receptor interactions with the bound ligand. Toward understanding molecular mechanisms of marijuana action, these X-ray crystal structures have shed light on how the ligand activates the receptor upon binding at the molecular level. It is seen in the X-ray crystal structure of the classical cannabinoid full agonist AM11542-bound CB1 receptor [6] that the dimethyl heptyl (DMH) tail of the ligand binds the hydrophobic channel (HC), disrupting the toggle switch of Phe200/Trp356 a pair of key aromatic residues.

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