In Vitro and In Silico Characterization of G-Protein Coupled Receptor (GPCR) Targets of Phlorofucofuroeckol-A and Dieckol
Abstract
:1. Introduction
2. Results
2.1. In Silico Target Prediction
2.2. Dieckol and PFF-A as A2AR Antagonists
2.3. Dieckol and PFF-A as α2CAR Agonists
2.4. Dieckol and PFF-A as δ-OPR Antagonists
2.5. PFF-A as a CB1R Agonist
2.6. Dieckol and PFF-A as GLP-1R Antagonists
2.7. Dieckol as Agonist and PFF-A as Antagonist of hV1AR
2.8. Dieckol and PFF-A as 5-HT1AR Antagonists
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Isolation of Phlorotannins
4.3. In Silico Prediction of Targets
4.4. Functional GPCR Assay
4.5. Measurement of cAMP Level
4.5.1. Functional Activity over hA2AR
4.5.2. Functional Activity over hα2CAR
4.5.3. Functional Activity over hCB1R
4.5.4. Functional Activity over GLP-1R
4.5.5. Functional Activity over 5-HT1BR
4.6. Measurement of Intracellular [Ca2+] Level
4.6.1. Functional Activity over hα2AAR
4.6.2. Functional Activity over hδ-OPR
4.6.3. Functional Activity over FFA1R/GPR40
4.6.4. Functional Activity over hV1AR
4.6.5. Functional Activity over h5-HT1AR
4.7. Homology Modeling and Molecular Docking
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
References
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Rank | Dieckol | Phlorofucofuroeckol-A | ||
---|---|---|---|---|
Protein Name | Average Score | Protein Name | Average Score | |
1 | Vasopressin 1A receptor | 0.513 | Vasopressin 1A receptor | 0.797 |
2 | Vasopressin 1B receptor | 0.742 | ||
3 | Oxytocin receptor | 0.737 | ||
4 | B2 bradykinin receptor | 0.735 | ||
5 | B1 bradykinin receptor | 0.727 | ||
6 | Histamine H1 receptor | 0.721 | ||
7 | Serotonin 1D receptor | 0.717 | ||
8 | Type-1 angiotensin II receptor | 0.716 | ||
9 | Dopamine D2 receptor | 0.713 | ||
10 | Cannabinoid receptor 1 | 0.711 | ||
11 | Prostanoid EP3 receptor | 0.710 | ||
12 | Rho-associated protein kinase 1 | 0.710 | ||
13 | Muscarinic acetylcholine receptor M3 | 0.709 | ||
14 | Cholecystokinin A receptor | 0.709 | ||
15 | Serotonin 1A receptor | 0.706 | ||
16 | Neurokinin 1 receptor | 0.706 | ||
17 | Cysteinyl leukotriene receptor 1 | 0.706 | ||
18 | Alpha-1D adrenergic receptor | 0.705 | ||
19 | Cholecystokinin B receptor | 0.704 | ||
20 | Serotonin 1B receptor | 0.704 |
GPCRs | Functional Effect at 100 µM Concentration | |||
---|---|---|---|---|
Dieckol | Phlorofucofuroeckol-A | |||
Agonist Effect | Antagonist Effect | Agonist Effect | Antagonist Effect | |
Adenosine A2A receptor (A2AR) | −0.1 ± 1.41 | 55.55 ± 4.03 | −0.7 ± 0.57 | 66.6 ± 2.26 |
Alpha-2A adrenergic receptor (α2AAR) | 13.4 ± 19.87 | 46.15 ± 20.15 | −0.5 ± 0.85 | 20.95 ± 1.77 |
Alpha-2C adrenergic receptor (α2CAR) | 52.4 ± 4.24 | −1.2 ± 6.08 | 83.8 ± 0.07 | 19.2 ± 9.76 |
δ-opioid receptor (δ-OPR) | −5.7 ± 0.14 | 66.95 ± 0.92 | 14.7 ± 7.35 | 73.55 ± 5.44 |
Cannabinoid receptor 1(CB1R) | −23.3 ± 12.09 | 158.75 ± 17.18 | 113.8 ± 3.68 | 21.35 ± 0.49 |
Free fatty acid receptor 1 (FFA1R) (GPR40) | 0.2 ± 1.56 | 22.55 ± 5.44 | −1.0 ± 0.07 | 30.15 ± 0.78 |
Glucagon-like peptide-1 receptor (GLP-1) | −16.3 ± 1.13 | 101 ± 8.20 | −15.5 ± 2.55 | 105.7 ± 1.27 |
Vasopressin 1A receptor (V1AR) | 106.73 ± 2.97 | 57.77 ± 0.32 b | 38.45 ± 7.14 a | 56.90 ± 5.37 b |
5-hydroxytryptophan 1A (5-HT1AR) | 1.75 ± 0.64 a | 91.0 ± 3.11 | 1.65 ± 0.49 a | 77.00 ± 11.03 |
5-hydroxytryptophan 1B (5-HT1BR) | −7.3 ± 3.96 | −18.5 ± 2.69 |
Compounds (µM) | Target GPCRs | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
hA2AR | hα2AAR | hα2CAR | hδ-OPR | CB1R | GPR40 | GLP-1 | hV1AR | h5-HT1AR | ||
Dieckol | 12.5 | – | – | – | – | – | – | – | – | – |
25 | – | – | – | – | – | – | – | – | – | |
50 | – | – | – | – | – | – | – | 50.40 ± 0.42 | – | |
100 | −0.1 ± 1.41 | 13.4 ± 19.87 | 52.4 ± 4.24 | −5.7 ± 0.14 | −23.3 ± 12.09 | 0.2 ± 1.56 | −16.3 ± 1.13 | 106.73 ± 2.97 | 1.75 ± 0.64 c | |
150 | – | – | 73.0 ± 6.42 | – | – | – | – | 118.1 ± 2.83 | – | |
200 | – | – | 74.77 ± 6.60 | – | – | – | – | – | – | |
EC50 (µM) a | NA | NA | 98.80 ± 7.71 | NA | NA | NA | NA | 39.12 ± 2.12 | NA | |
PFF-A | 12.5 | – | – | 22.03 ± 6.61 | – | 46.7 ± 6.22 | – | – | – | – |
25 | – | – | 55.0 ± 9.13 | – | 80.3 ± 4.10 | – | – | – | – | |
50 | – | – | 62.27 ± 6.53 | – | 96.45 ± 5.02 | – | – | – | – | |
100 | −0.7 ± 0.57 | −0.5 ± 0.85 | 83.8 ± 0.07 | 14.7 ± 7.35 | 113.8 ± 3.68 | −1.0 ± 0.07 | −15.5 ± 2.55 | 38.45 ± 7.14 c | 1.65 ± 0.49 c | |
150 | – | – | – | – | – | – | – | – | – | |
200 | – | – | – | – | – | – | – | – | – | |
EC50 (µM) a | NA | NA | 23.67 ± 3.32 | NA | 13.42 ± 2.03 | NA | NA | NA | NA | |
Reference Drugs, EC50 (nM) b | 9.1 | 0.74 | 0.86 | 4.4 | 0.21 | 10000 | 0.049 | 0.72 | 2.5 c |
Compounds (µM) | Target GPCRs | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
hA2AR | hα2AAR | hα2CAR | hδ-OPR | CB1R | GPR40 | GLP-1 | hV1AR | h5-HT1AR | h5-HT1BR | ||
Dieckol | 12.5 | – | – | – | – | – | – | 17.87 ± 6.32 | – | – | – |
25 | – | – | – | – | – | – | 21.23 ± 7.31 | – | – | – | |
50 | 17.5 ± 8.50 | – | – | 23.23 ± 4.04 | – | – | 53.80 ± 3.12 | 41.53 ± 7.39 c | 54.7 ± 1.7 | – | |
100 | 56.0 ± 11.11 | 46.15 ± 20.15 | −1.20 ± 6.08 | 71.6 ± 17.85 | −1.20 ± 6.08 | 22.55 ± 5.44 | 101.0 ± 8.20 | 57.77 ± 0.32 c | 91.0 ± 3.11 | −7.3 ± 3.96 | |
150 | 62.43 ± 12.19 | – | – | 100.1 ± 1.53 | – | – | – | 68.80 ± 0.85 c | – | – | |
200 | – | – | – | – | – | – | – | – | 100.9 ± 0.57 | −8.1 ± 0.85 | |
IC50 (µM) a | 87.18 ± 2.63 | NA | NA | 80.46 ± 13.74 | NA | NA | 47.19 ± 2.46 | 82.71 ± 8.73 | 43.31 ± 3.22 | NA | |
PFF-A | 12.5 | – | – | – | – | – | – | 25.63 ± 13.14 | – | 37.40 ± 2.19 | – |
25 | – | – | – | – | – | – | 57.37 ± 1.15 | 35.67 ± 3.88 | 68.20 ± 9.89 | – | |
50 | 64.7 ± 2.72 | – | – | 89.03 ± 0.70 | – | – | 83.87 ± 2.03 | 52.80 ± 8.09 | 85.55 ± 8.41 | – | |
100 | 92.2 ± 0.95 | 20.95 ± 1.77 | 19.2 ± 9.76 | 96.47 ± 0.84 | 21.35 ± 0.49 | 30.15 ± 0.78 | 105.7 ± 1.27 | 56.90 ± 5.37 c | 77.00 ± 11.03 | −18.5 ± 2.69 | |
150 | 99.93 ± 0.31 | – | – | 93.67 ± 6.67 | – | – | – | 56.07 ± 4.72 | – | – | |
200 | – | – | – | – | – | – | – | – | – | −35.5 ± 4.38 | |
IC50 (µM) a | < 50 | NA | NA | < 50 | NA | NA | 21.56 ± 2.16 | 42.25 ± 0.41 | 17.75 ± 3.42 | NA | |
Reference Drugs, IC50 (nM) b | 0.41 | 17 | 22 | 9 | 77 | ND | 4.6 | 1.9 | 4.4 | 23 |
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Paudel, P.; Seong, S.H.; Park, S.E.; Ryu, J.H.; Jung, H.A.; Choi, J.S. In Vitro and In Silico Characterization of G-Protein Coupled Receptor (GPCR) Targets of Phlorofucofuroeckol-A and Dieckol. Mar. Drugs 2021, 19, 326. https://doi.org/10.3390/md19060326
Paudel P, Seong SH, Park SE, Ryu JH, Jung HA, Choi JS. In Vitro and In Silico Characterization of G-Protein Coupled Receptor (GPCR) Targets of Phlorofucofuroeckol-A and Dieckol. Marine Drugs. 2021; 19(6):326. https://doi.org/10.3390/md19060326
Chicago/Turabian StylePaudel, Pradeep, Su Hui Seong, Se Eun Park, Jong Hoon Ryu, Hyun Ah Jung, and Jae Sue Choi. 2021. "In Vitro and In Silico Characterization of G-Protein Coupled Receptor (GPCR) Targets of Phlorofucofuroeckol-A and Dieckol" Marine Drugs 19, no. 6: 326. https://doi.org/10.3390/md19060326