In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists

Zheng, Yaxin; Wu, Jiming; Feng, Xuesong; Jia, Ying; Huang, Jian; Hao, Zhihui; Zhao, Songyan; Wang, Jinhui

doi:10.1371/journal.pone.0130055

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…Notably, a number of following docking studies reported in literature described a unique receptor cavity involved in the 5-HT 1A full agonists, partial agonists and antagonists binding [58][59][60], giving a further validation to our previous computational findings. Indeed, H-bond interactions between agonists and D116 and N386 were reported in literature, falling in a crevice delimited by F112, I113, D116, K191, while partial agonists as well as antagonists were Hbonded at least with D116.…”

Section: -Ht 1a R Docking-studiessupporting

confidence: 86%

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Franchini

Manasieva

Sorbi

et al. 2017

European Journal of Medicinal Chemistry

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Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HTR agonist with a moderate 5-HTR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HTR and α adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HTR partial agonists, the first being outstanding for selectivity (5-HT/α = 80), the latter for potency (pD = 9.58) and efficacy (E = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

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Section: -Ht 1a R Docking-studiessupporting

confidence: 86%

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Franchini

Manasieva

Sorbi

et al. 2017

European Journal of Medicinal Chemistry

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“…We then utilized the SEA database (Zheng et al. 2015 ) for determining targets of the MHT compounds. Here, to predict potential targets of MHT, we used a similarity-based method, the core idea of which is to rank potential compound-target interactions based on their similarity to known compound-target interactions.…”

Section: Methodsmentioning

confidence: 99%

Ma Huang Tang ameliorates bronchial asthma symptoms through the TLR9 pathway

Jiao

Wang

et al. 2018

Pharmaceutical Biology

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Context: Ma Huang Tang (MHT) has been used to treat influenza, fever, bronchial asthma, etc. as a traditional Chinese medication. However, the anti-inflammation mechanism of MHT remains unclear.Objective: The study identifies the possible mechanisms of MHT on ovalbumin (OVA)-induced acute bronchial asthma in mice.Materials and methods: First, an asthma-related protein-protein interaction (PPI) network was constructed. And then, the acute bronchial asthma mice models were established by exposing to aerosolized 1% ovalbumin for 30 min/day for 1 week, and the mice were administered 2.0, 4.0, or 8.0 g/kg of MHT daily. To evaluate therapeutic effect, sensitization time, abdominal breathing time, eosinophils in bronchoalveolar lavage fluid, and tissue and trachea pathology were examined. Related genes were measured using RNA sequencing (RNA-seq). The expression levels of TLR9 in lung and trachea tissues were determined by immunohistochemical staining.Results: MHT had a LD50 = 19.2 g/kg against asthma, while MHT at high doses (8 g/kg) effectively extended the sensitization time and abdominal breathing time and alleviated OVA-induced eosinophilic airway inflammation and mitigated pathological changes. The RNA-seq assay showed that the high-dose MHT resulted in a significant decrease in the levels of TLR9, TRAF6, TAB2, etc. in the lung tissue. Immunohistochemical assay confirmed the down-regulated of TLR9. Molecular docking revealed that six MHT compounds potentially mediated the TLR9 signaling pathway.Discussion and conclusions: MHT could mitigate the pathological changes of acute asthma-like syndrome through inhibition of the TLR9 pathway. Results of this study may provide a reference for the development of a novel therapy for patients with allergic asthma.

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“…Additional studies were aimed to conduct docking in 5HT receptors 5HT 1a , 5HT 2a e 5HT 3 . To reach this goal, the amino acid sequence of 5HT 1a was downloaded from UniProt database (accession code: P08908, 5HT1A_HUMAN) and the 3D structure of 5-HT1AR was constructed using the SWISS-MODEL server according to Zheng et al (2015) [ 38 ]. 5HT 2a receptor was similarly built from 5HT 2b and the amino acid sequence of 5HT 2a Uniprot database (accession code: P28223) according to Gandhimathi and Sowdhamini, (2015) [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

et al. 2017

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A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

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In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists

Cited by 10 publications

References 52 publications

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Ma Huang Tang ameliorates bronchial asthma symptoms through the TLR9 pathway

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

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