Functional, electrophysiology, and molecular dynamics analysis of quercetin-induced contraction of rat vascular musculature

Trezza, Alfonso; Spiga, Ottavia; Mugnai, Paolo; Saponara, Simona; Sgaragli, Giampietro; Fusi, Fabio

doi:10.1016/j.ejphar.2022.174778

Cited by 19 publications

(6 citation statements)

References 49 publications

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“…The Rattus norvegicus Ca V 1.2 channel subunit α 1C 3D structure was achieved with a homology modelling procedure, as described by Trezza et al [ 47 ]. The primary structure of Rattus norvegicus K Ca 1.1 channel, downloaded by Uniprot Database (UniProt ID - Q62976 -), was used as a query sequence for a multiple sequences alignment (MSA) carried out using Clustal Omega, implemented in PyMOD3.0 [ 48 ], and choosing Protein Data Bank (pdb) as the Database; all algorithm parameters were used as default.…”

Section: Methodsmentioning

confidence: 99%

“…tool [ 53 ]. A classical molecular dynamics (cMD) simulation of 100 ns was performed on the Ca V 1.2 channel in the free state and in complex with the compounds, to investigate the potential binding mode of the compounds, as previously described [ 47 ]. In brief, CHARMM-GUI platform [ 17 ] was used to insert the system inside POPCs 128 (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) bilayer, solvated with TIP3P water models and neutralized with counter-ions.…”

Section: Methodsmentioning

confidence: 99%

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Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

et al. 2022

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Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

et al. 2022

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“…The Rattus norvegicus Ca V 1.2 channel’s subunit α 1C ’s 3D structure was achieved with a homology modelling procedure as described by Trezza et al [ 26 ]. The rabbit inactive Ca V 1.1 channel’s 3D structure (PDB code 6JPA) in complex with its blocker verapamil, recently obtained through cryoEM by Zhao et al [ 27 ], was selected as a template to build the Ca V 1.2 3D model and explore the structural and energetic features of the compounds binding to the channel.…”

Section: Methodsmentioning

confidence: 99%

“…In brief, a box of 22 Å for each dimension was generated for the Ca V 1.2 channel, enclosing a known blocker binding region of the protein [ 27 ]. To investigate the potential mechanism of action, a classical molecular dynamics (cMD) simulation of 100 ns was performed on the channel bound to the compounds as previously reported [ 26 ]. A box of 18 Å for each dimension was generated for the K Ca 1.1 channel, enclosing a stimulator binding region as previously described [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Vietnamese Dalbergia tonkinensis: A Promising Source of Mono- and Bifunctional Vasodilators

et al. 2022

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Hypertension is a risk factor for cardiovascular diseases, which are the main cause of morbidity and mortality in the world. In the search for new molecules capable of targeting KCa1.1 and CaV1.2 channels, the expression of which is altered in hypertension, the in vitro vascular effects of a series of flavonoids extracted from the heartwoods, roots, and leaves of Dalbergia tonkinensis Prain, widely used in traditional medicine, were assessed. Rat aorta rings, tail artery myocytes, and docking and molecular dynamics simulations were used to analyse their effect on these channels. Formononetin, orobol, pinocembrin, and biochanin A showed a marked myorelaxant activity, particularly in rings stimulated by moderate rather than high KCl concentrations. Ba2+ currents through CaV1.2 channels (IBa1.2) were blocked in a concentration-dependent manner by sativanone, 3′-O-methylviolanone, pinocembrin, and biochanin A, while it was stimulated by ambocin. Sativanone, dalsissooside, and eriodictyol inhibited, while tectorigenin 7-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside], ambocin, butin, and biochanin A increased IKCa1.1. In silico analyses showed that biochanin A, sativanone, and pinocembrin bound with high affinity in target-sensing regions of both channels, providing insight into their potential mechanism of action. In conclusion, Dalbergia tonkinensis is a valuable source of mono- and bifunctional, vasoactive scaffolds for the development of novel antihypertensive drugs.

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“…The compoundʼs charges were assigned with Epik at pH 7.00 ± 1.00 in agreement with the OPLS4 force field [37]. The homology model of the Rattus norvegicus Ca V 1.2 channel α 1C subunit, as obtained from previous calculations [38], was adopted for the following in silico simulations. The Rattus norvegicus K Ca 1.1 channel three-dimensional structure was rebuilt as previously described [39] by homology modelling, starting from the Cryo-EM model of the human K Ca 1.1 channel (6V22 entry of the protein data bank) at 3.2 Å resolution [23].…”

Section: Protein and Ligand Preparationmentioning

confidence: 99%

Vasorelaxant Activity of (2S)-Sakuranetin and Other Flavonoids Isolated from the Green Propolis of the Caatinga Mimosa tenuiflora

Son,

Gianibbi,

Panti

et al. 2024

Planta Med

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Some in vitro and in vivo evidence is consistent with the cardiovascular beneficial activity of propolis. As the single actors responsible for this effect have never been identified, an in-depth investigation of flavonoids isolated from the green propolis of the Caatinga Mimosa tenuiflora was performed and their mechanism of action was described. A comprehensive electrophysiology, functional, and molecular docking approach was applied. Most flavanones and flavones were effective CaV1.2 channel blockers with a potency order of (2S)-sakuranetin > eriodictyol-7,3′-methyl ether > quercetin 3-methyl ether > 5,4′-dihydroxy-6,7-dimethoxyflavanone > santin > axillarin > penduletin > kumatakenin, ermanin and viscosine being weak or modest stimulators. Except for eriodictyol 5-O-methyl ether, all the flavonoids were also effective spasmolytic agents of vascular rings, kumatakenin and viscosine also showing an endothelium-dependent activity. (2S)-Sakuranetin also stimulated KCa1.1 channels both in single myocytes and vascular rings. In silico analysis provided interesting insights into the mode of action of (2S)-sakuranetin within both CaV1.2 and KCa1.1 channels. The green propolis of the Caatinga Mimosa tenuiflora is a valuable source of multi-target vasoactive flavonoids: this evidence reinforces its nutraceutical value in the cardiovascular disease prevention arena.

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Functional, electrophysiology, and molecular dynamics analysis of quercetin-induced contraction of rat vascular musculature

Cited by 19 publications

References 49 publications

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

Vietnamese Dalbergia tonkinensis: A Promising Source of Mono- and Bifunctional Vasodilators

Vasorelaxant Activity of (2S)-Sakuranetin and Other Flavonoids Isolated from the Green Propolis of the Caatinga Mimosa tenuiflora

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