Network-Based Pharmacology Study Reveals Protein Targets for Medical Benefits and Harms of Cannabinoids in Humans
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Acquisition and Processing
2.2. Network Construction and Module Identification
2.3. Contribution Score Calculation
2.4. Integrated Centrality Calculation
2.5. Molecular Docking
3. Results and Discussion
3.1. Key Cannabinoids
3.2. Drug-Like Properties of the Selected Cannabinoids
3.3. C-T Network Construction and Analysis
3.4. PPI Network Construction and Analysis
3.5. GO Biological Function and KEGG Pathway Enrichment Analysis
3.6. Network Construction and Module Identification
3.7. Contribution Scores
3.8. Integrated Centrality and Essential Protein Targets
3.9. Molecule Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
∆9-THC | ∆9-tetrahydrocannabinol |
∆8-THC | ∆8-tetrahydrocannabinol |
11-OH-∆9-THC | 11-hydroxy-∆9- tetrahydrocannabinol |
∆9-THCA | ∆9-tetrahydrocannabinolic acid |
∆9-THCV | ∆9-tetrahydrocannabivarin |
THCVA | tetrahydrocannabivarinic acid |
CBN | cannabinol |
CBD | cannabidiol |
CBDA | cannabidiolic acid |
CBDV | cannabidivarin |
CBDVA | cannabidivarinic acid |
CBC | cannabichromene |
CBCA | cannabichromenic acid |
CBCVA | cannabichromevarinic acid |
CBG | cannabigerol |
CBGA | cannabigerolic Acid |
CBGVA | cannabigevarolic acid |
CAT | catalase |
COMT | catechol-O-methyltransferase |
CYP17A1 | cytochrome P450 family 17 subfamily A member 1 |
GSTA2 | glutathione S-transferase alpha 2 |
GSTM3 | glutathione S-transferase mu 3 |
GSTP1 | glutathione S-transferase pi 1 |
HMOX1 | heme oxygenase 1 |
AKT1 | AKT serine/threonine kinase 1 |
CASP9 | caspase 9 |
PLCG1 | phospholipase C gamma 1 |
PRKCA | protein kinase C alpha |
PRKCB | protein kinase C beta |
CYCS | cytochrome c, somatic |
TNF | tumor necrosis factor |
CNR1 | cannabinoid receptor 1 |
CNR2 | cannabinoid receptor 2 |
CREB1 | cAMP responsive element binding protein 1 |
GRIN2B | glutamate ionotropic receptor NMDA type subunit 2B |
GO | the Gene Ontology |
KEGG | the Kyoto Encyclopedia of Genes and Genomes |
ETCM | the Encyclopedia of Traditional Chinese Medicine |
TCMSP | Traditional Chinese Medicine Systems Pharmacology |
ADMET | Absorption, distribution, metabolism, excretion, and toxicity |
DL | drug-likeness |
BBB | blood-brain ratio |
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(A) | ||
---|---|---|
NO. | Disease | References |
1 | Alzheimer’s disease | [7] |
2 | Amyotrophic lateral sclerosis (ALS) | [8] |
3 | Anorexia | [7,9] |
4 | Cancer | [8,10] |
5 | Chronic spasticity | [11] |
7 | Crohn’s disease | [8] |
8 | Cutaneous treatment (dermatitis, Sebum’s excess & acne, epidermolysis bullosa, Kaposi sarcoma, metastatic melanoma) | [7] |
9 | Epilepsy | [8,9,11,12] |
10 | Glaucoma | [7,9,13] |
11 | HIV | [8,11] |
12 | Huntington disease | [11] |
13 | Infectious Diseases | [7] |
14 | Inflammation | [8,9,11,13] |
15 | Inflammatory bowel syndrome (IBS) | [8] |
16 | Insomnia | [7,11,14] |
17 | Ischemic stroke | [8,15] |
18 | Malaria | [15] |
19 | Multiple sclerosis | [7,8,9,11,13] |
20 | Nausea and vomiting | [7,8,9,11,14] |
21 | Anxiety disorders and obsessive-compulsive disorders | [8] |
22 | Osteoarthritis | [16] |
23 | Pain | [7,8,9,11,13] |
24 | Parkinson’s disease | [7,8] |
25 | Post-traumatic stress disorder (PTSD) | [7] |
26 | Tourette’s Syndrome | [7,11] |
27 | Uremic pruritus | [14] |
28 | Respiratory diseases: airflow obstruction, bronchitis, airway injury | [13,17] |
(B) | ||
NO. | Disease | References |
1 | Impairment of brain development of fetus and adolescence, impaired brain connectivity, cognitive and motor functions, learning ability, and memory | [8,9,11,13] |
2 | Psychiatric comorbidities: depression, anxiety, dysphoria, delusions, bipolar disorder | [9,11,13] |
3 | Schizophrenia: hallucinations, paranoia, and disorganized thinking | [8,9,11,17] |
4 | Cannabis use disorders and withdrawal symptoms: dizziness, dry mouth, somnolence, and confusion; restless, irritability, mild agitation, insomnia, nausea, and cramping | [9,10,14] |
5 | Cannabinoid hyperemesis syndrome: nausea, vomiting, and dehydration | [18] |
6 | Addiction/substance dependence | [8,11,13] |
No. | Target | Description | Uniprot | IC | Module | Cannabinoid Ligands |
---|---|---|---|---|---|---|
1 | CAT | Catalase | P04040 | 0.63 | 1 | CBD, CBDA |
2 | COMT | Catechol-O-methyltransferase | P21964 | 0.57 | 1 | Δ9-THC, CBN |
3 | CYP17A1 | Cytochrome P450 family 17 subfamily A member 1 | P05093 | 0.56 | 1 | CBD, CBDA |
4 | GSTA2 | Glutathione S-transferase alpha 2 | P09210 | 0.51 | 1 | Δ9-THC, CBC, CBN |
5 | GSTM3 | Glutathione S-transferase mu 3 | P21266 | 0.64 | 1 | Δ9-THC, CBC, CBN |
6 | GSTP1 | Glutathione S-transferase pi 1 | P09211 | 0.72 | 1 | Δ9-THC, CBC, CBN |
7 | HMOX1 | Heme oxygenase 1 | P09601 | 0.52 | 1 | Δ9-THC, CBC, CBN |
8 | AKT1 | AKT serine/threonine kinase 1 | P31749 | 0.81 | 2 | CBD, CBDA |
9 | CASP9 | Caspase 9 | P55211 | 0.67 | 2 | CBD, CBDA |
10 | PLCG1 | Phospholipase C gamma 1 | P19174 | 0.51 | 2 | CBGA |
11 | PRKCA | Protein kinase C alpha | P17252 | 0.65 | 2 | Δ9-THC, CBC, CBD, CBDA, CBN |
12 | PRKCB | Protein kinase C beta | P05771 | 0.56 | 2 | Δ9-THC, CBC, CBN |
13 | CYCS | Cytochrome c, somatic | P99999 | 0.59 | 3 | CBG |
14 | TNF | Tumor necrosis factor | P01375 | 0.55 | 3 | Δ8-THC, CBD, CBDA |
15 | CNR1 | Cannabinoid receptor 1 | P21554 | 0.20 | 4 | ∆8-THC, ∆9-THC, CBC, CBD, CBDA, CBG, CBGA, CBN |
16 | CNR2 | Cannabinoid receptor 2 | P34972 | 0.20 | 4 | ∆8-THC, ∆9-THC, CBC, CBD, CBDA, CBG, CBGA, CBN |
17 | CREB1 | cAMP-responsive element binding protein 1 | P16220 | 0.63 | 4 | Δ9-THC, CBN |
18 | GRIN2B | Glutamate ionotropic receptor NMDA type subunit 2B | Q13224 | 0.68 | 4 | Δ9-THC, Δ8-THC |
Ligands | ∆8-THC | ∆9-THC | CBC | CBD | CBDA | CBG | CBGA | CBN | |
---|---|---|---|---|---|---|---|---|---|
Target (PDB-ID) | |||||||||
AKT1 (6S9W) | / | / | / | -8.6 | −8.8 | / | / | / | |
CASP9 (4RHW) | / | / | / | −5.8 | −5.9 | / | / | / | |
CAT (1DGF) | / | / | / | −7.5 | −7.9 | / | / | / | |
COMT (4PYI) | / | −8.0 | / | / | / | / | / | −8.0 | |
CREB1 (5ZKO) | / | −5.8 | / | / | / | / | / | −6.6 | |
CYCS (5TY3) | / | / | / | / | / | −4.7 | / | / | |
CYP17A1 (6WR1) | / | / | / | −7.4 | −7.0 | / | / | / | |
GRIN2B (5EWM) | −7.6 | −8.0 | / | / | / | / | / | / | |
GSTA2 (5LD0) | / | −7.0 | −5.4 | / | / | / | / | −6.5 | |
GSTM3 (3GTU) | / | −7.7 | −6.7 | / | / | / | / | −7.6 | |
GSTP1 (5J41) | / | −8.7 | −7.6 | / | / | / | / | −8.1 | |
HMOX1 (1N45) | / | −8.0 | −7.4 | / | / | / | / | −7.7 | |
PLCG1 (3GQI) | / | / | / | / | / | / | −5.6 | / | |
PRKCA (4RA4) | / | −7.5 | −7.8 | −6.7 | −7.4 | / | / | −8.2 | |
PRKCB (2I0E) | / | −8.1 | −8.1 | / | / | / | / | −8.5 | |
TNF (6OOY) | −10.4 | / | / | −6.0 | −10.5 | / | / | / | |
CNR1 (5U09) | −7.9 | −7.6 | −7.0 | −7.3 | −7.1 | −7.9 | −6.9 | −9.4 | |
CNR2 (6KPC) | −8.0 | −8.2 | −7.7 | −9.2 | −7.3 | −6.9 | −7.0 | −8.5 |
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Li, X.; Madhukar Kudke, A.; Joseph Nepveux V, F.; Xu, Y. Network-Based Pharmacology Study Reveals Protein Targets for Medical Benefits and Harms of Cannabinoids in Humans. Appl. Sci. 2022, 12, 2205. https://doi.org/10.3390/app12042205
Li X, Madhukar Kudke A, Joseph Nepveux V F, Xu Y. Network-Based Pharmacology Study Reveals Protein Targets for Medical Benefits and Harms of Cannabinoids in Humans. Applied Sciences. 2022; 12(4):2205. https://doi.org/10.3390/app12042205
Chicago/Turabian StyleLi, Xingyu, Amit Madhukar Kudke, Felix Joseph Nepveux V, and Yan Xu. 2022. "Network-Based Pharmacology Study Reveals Protein Targets for Medical Benefits and Harms of Cannabinoids in Humans" Applied Sciences 12, no. 4: 2205. https://doi.org/10.3390/app12042205