Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Yoshida, Takuya; Oki, Hiroya; Doi, Masamitsu; Fukuda, Syohei; Yuzuriha, Tomohiro; Tabata, Ryotaro; Ishimoto, Kenji; Kawahara, Kazuki; Ohkubo, Tadayasu; Miyachi, Hiroyuki; Doi, Takefumi; Tachibana, Keisuke

doi:10.1038/s41598-020-64527-x

Cited by 6 publications

(5 citation statements)

References 31 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Particularly, the interaction between Tyr464 and the ligands has been found to be crucial for regulating the co-activator recruitment. Such an interaction, together with other H-bonds involving three polar residues that are highly conserved in the arm I of each PPAR isotype (Ser280, Tyr314, and His440 in PPAR-α) [10], has been proposed to hold the AF2 helix in the active conformation which is permissive for interactions with co-activators [11].…”

Section: Analogues Of Pea Can Equally Bind Ppar-α Receptormentioning

confidence: 99%

Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

D’Aloia

Arrigoni

Tisi

et al. 2020

IJMS

View full text Add to dashboard Cite

Palmitoylethanolamide (PEA) belongs to the class of N-acylethanolamine and is an endogenous lipid potentially useful in a wide range of therapeutic areas; products containing PEA are licensed for use in humans as a nutraceutical, a food supplement, or food for medical purposes for its analgesic and anti-inflammatory properties demonstrating efficacy and tolerability. However, the exogenously administered PEA is rapidly inactivated; in this process, fatty acid amide hydrolase (FAAH) plays a key role both in hepatic metabolism and in intracellular degradation. So, the aim of the present study was the design and synthesis of PEA analogues that are more resistant to FAAH-mediated hydrolysis. A small library of PEA analogues was designed and tested by molecular docking and density functional theory calculations to find the more stable analogue. The computational investigation identified RePEA as the best candidate in terms of both synthetic accessibility and metabolic stability to FAAH-mediated hydrolysis. The selected compound was synthesized and assayed ex vivo to monitor FAAH-mediated hydrolysis and to confirm its anti-inflammatory properties. 1H-NMR spectroscopy performed on membrane samples containing FAAH in integral membrane protein demonstrated that RePEA is not processed by FAAH, in contrast with PEA. Moreover, RePEA retains PEA’s ability to inhibit LPS-induced cytokine release in both murine N9 microglial cells and human PMA-THP-1 cells.

show abstract

Section: Analogues Of Pea Can Equally Bind Ppar-α Receptormentioning

confidence: 99%

Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

D’Aloia

Arrigoni

Tisi

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Molecular docking was conducted to validate the results of the network analysis. Epidermal growth factor receptor (EGFR) (PDB ID: 7B85 ; deposited by [ 42 ], [ 43 ]), mitogen-activated protein kinase 14 (MAPK14) (PDB ID: 6HWU ; deposited by [ 44 ], [ 45 ]), and peroxisome proliferator activated receptor alpha (PPARA) (PDB ID: 6KXY ; deposited by [ 46 ], [ 47 ]) were selected as the proteins. The selection was made based on the results of target identification, MCC scores, and involvement in the most enriched pathway.…”

Section: Methodsmentioning

confidence: 99%

Analysis of the anti-Alzheimer potential of bioactive compounds from Citrus hystrix DC. peel, leaf, and essential oil by network pharmacology

Putri,

Utomo,

Tunjung

et al. 2024

Heliyon

View full text Add to dashboard Cite

“…The crucial amino acid residues actively involved in the agonist binding of the nociceptive receptors were retrieved from the literature. [30][31][32][33] AutoDock tool was utilized to generate grids, calculate dock score, and evaluate the conformers of BCP interacting in the binding sites of receptors. The grid map parameters were generated with AutoGrid (Table 1).…”

Section: Molecular Dockingmentioning

confidence: 99%

ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels

Venkatakrishna¹,

K²,

HV³

et al. 2022

JPR

View full text Add to dashboard Cite

Plant-based natural products as anti-nociceptors have enormous potential as safer alternatives to conventional opiates and NSAIDS. Piper nigrum (black pepper) is one of the major culinary spices with medicinal attributes. Methods: In the present study, the antinociceptive activity of a standardized black pepper seed extract (Viphyllin) containing not less than 30% β-caryophyllene (BCP) was evaluated using pain models in mice, namely acetic acid-induced writhing test, formalin-induced paw licking test, hot plate test and tail flick test. Further, the antagonists SR141716A (0.1 mg/kg i.p.), AM630 (5 mg/kg i.p.), capsazepine (0.1 mg/kg body weight i.p.), and GW6471 (1 mg/kg i.p.) were used to evaluate the involvement of cannabinoid receptors CB1 and CB2, TRPV1 ion channel and PPARα receptor, respectively. Molecular docking (AutoDock 4.2) was used to study the interaction of BCP with the agonist-binding sites of the selected pain receptors. Results: Viphyllin at 10 mg, 25 mg and 50 mg/kg (i.p.) significantly inhibited the writhings in mice as compared to untreated control group (p < 0.001). Further, Viphyllin at 50 mg/kg showed strong antinociceptive effect in formalin-induced paw licking test (p < 0.05). Pretreatment of mice with AM630 significantly reversed the antinociceptive activity of Viphyllin in both early and late phases of formalin test (p < 0.05). Administration of Viphyllin markedly increased the latency time of mice in hot plate test (p < 0.001). Further, Viphyllin markedly increased the latency time of tail flick compared to control group from 30 min to 90 min after treatment. AM630, Capsazepine, and GW6471 abolished the analgesic effect of Viphyllin. These findings clearly suggest the involvement of CB2 receptor, TRPV1 ion channel and PPARα receptor activation in Viphyllin-mediated antinociceptive activity. Docking score predictions further supported the possible involvement of BCP in the antinociceptive mechanism of Viphyllin. Conclusion:In conclusion, Viphyllin could be a natural pain-relieving agent involving safer pain signaling mechanisms, unlike conventional opiates and NSAIDs.

show abstract

Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Cited by 6 publications

References 31 publications

Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

Analysis of the anti-Alzheimer potential of bioactive compounds from Citrus hystrix DC. peel, leaf, and essential oil by network pharmacology

ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels

Contact Info

Product

Resources

About