Computational systems pharmacology analysis of cannabidiol: a combination of chemogenomics-knowledgebase network analysis and integrated in silico modeling and simulation

Abstract

With treatment benefits in both the central nervous system and the peripheral system, the medical use of cannabidiol (CBD) has gained increasing popularity. Given that the therapeutic mechanisms of CBD are still vague, the systematic identification of its potential targets, signaling pathways, and their associations with corresponding diseases is of great interest for researchers. In the present work, chemogenomics-knowledgebase systems pharmacology analysis was applied for systematic network studies to generate CBD-target, target-pathway, and target-disease networks by combining both the results from the in silico analysis and the reported experimental validations. Based on the network analysis, three human neuro-related rhodopsin-like GPCRs, i.e., 5-hydroxytryptamine receptor 1 A (5HT_1A), delta-type opioid receptor (OPRD) and G protein-coupled receptor 55 (GPR55), were selected for close evaluation. Integrated computational methodologies, including homology modeling, molecular docking, and molecular dynamics simulation, were used to evaluate the protein-CBD binding modes. A CBD-preferred pocket consisting of a hydrophobic cavity and backbone hinges was proposed and tested for CBD-class A GPCR binding. Finally, the neurophysiological effects of CBD were illustrated at the molecular level, and dopamine receptor 3 (DRD3) was further predicted to be an active target for CBD.

Keywords: 5HT1A; D3; cannabidiol (CBD); cannabinoid; homology modeling; molecular docking; molecular dynamics simulation; systems pharmacology.

Fig. 1

A schematic representation of the workflow in this study

Fig. 2

Chemogenomics-based targets mapping for CBD. The size of the balloons is correlated with the predicted affinity between the target and CBD. Balloons with pink color represent the purely predicted targets. Balloons with green color represent the experimentally validated targets. Balloons with yellow color represent the known targets

Fig. 3

CBD target-pathway network. Blue nodes represent the targets for CBD identified through target mapping. Yellow and orange nodes represent signaling pathways or processes. In particular, orange nodes are shared by three or more targets and placed in the center for emphasis. Targets are connected with pathways or processes with edges in the corresponding color

Fig. 4

CBD target-disease network. Blue nodes represent the targets for CBD identified through target mapping. Salmon and pink nodes represent different diseases. Pink nodes are neurological-related diseases and are placed in the center for emphasis. Targets are connected with diseases with edges in the corresponding color

Fig. 5

Simulated binding mode of CBD on GPR55. The protein is shown as a cartoon. CBD (cyan) and critical residues (yellow) involved in interactions and pocket formation are shown in sticks. H-bonds are marked as red dashes, and hydrophobic interactions are marked as blue dashes. a CBD-GPR55 binding follows a hydrophobic cavity and backbone hinge model. Cyan spheres represent the location of the hydrophobic cavity. Red spheres represent the location of the hinge formation. b Static docking pose and ligand-residue interactions between the GPR55 protein model and CBD. c Pose and ligand-residue interactions between the GPR55 protein model and CBD for the coordinate at 120 ns (equilibrium stage) during the molecular dynamics simulation

Fig. 6

Simulated binding mode of CBD on 5HT_1A. The protein is shown as a cartoon. CBD (cyan) and critical residues (yellow) involved in interactions and pocket formation are shown in sticks. H-bonds are marked as red dashes, and hydrophobic interactions are marked as blue dashes. a CBD-5HT_1A binding follows a model of hydrophobic cavity and backbone hinge. Cyan spheres represent the location of the hydrophobic cavity. Red spheres represent the location of the hinge formation. b Static docking pose and ligand-residue interactions between the 5HT_1A protein model and CBD. c Pose and ligand-residue interactions between the 5HT_1A protein model and CBD for the coordinate at 100 ns (equilibrium stage) during the molecular dynamics simulation

Fig. 7

Simulated binding mode of CBD on OPRD. The protein is shown as a cartoon. CBD (cyan) and critical residues (yellow) involved in interactions and pocket formation are shown in sticks. H-bonds are marked as red dashes, and hydrophobic interactions are marked as blue dashes. a CBD-OPRD binding follows a model of hydrophobic cavity and backbone hinge. Cyan spheres represent the location of the hydrophobic cavity. Red spheres represent the location of the hinge formation. b Static docking pose and ligand-residue interactions between the OPRD protein model and CBD. c Pose and ligand-residue interactions between the OPRD protein model and CBD for the coordinate at 30 ns (first equilibrium stage) during the molecular dynamics simulation. d Extracellular view of pose and ligand-residue interactions between the OPRD protein model and CBD for the coordinate at 160 ns (second equilibrium stage) during the molecular dynamics simulation

Fig. 8

The 200-ns molecular dynamics simulation for the CBD-protein complexes. a Simulation system for the CBD-GPR55 protein model complex, with water in red spots, chlorine ions in green balls, sodium ions in yellow balls, membrane in cyan sticks, protein in purple cartoon, and CBD in cyan sticks. b RMSD change for both CBD and the GPR55 protein model. c Simulation system for the CBD-5HT_1A protein model complex. d RMSD change for both CBD and the 5HT_1A protein model. e Simulation system for the CBD-OPRD protein model complex. f RMSD change for both CBD and the OPRD protein model

Fig. 9

CBD-D3 protein model binding pose and negative controls. Proteins are shown in cartoon format in green. CBD is marked in cyan. Critical residues involved in interactions and pocket formation are marked in yellow. a Membrane and extracellular views of docking pose and ligand-residue interactions between the D3 protein model and CBD. b Membrane and extracellular views of docking pose and ligand-residue interactions between the A2A protein model and CBD. c Membrane and extracellular views of docking pose and ligand–residue interactions between the CXCR4 protein model and CBD