Cardiotonic steroids as potential Na+/K+-ATPase inhibitors – a computational study

Patel, Chirag; Kumar, Sivakumar Prasanth; Modi, Krunal; Soni, Mehul N.; Modi, Nainesh; Pandya, Himanshu

doi:10.1080/10799893.2019.1660893

Cited by 23 publications

(13 citation statements)

References 41 publications

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“…Cardenolides have been used for the treatment of congestive heart failure and atrial arrhythmias (Scalese and Salvatore 2017; Whayne 2018). They act as inhibitors of the Na + /K + -ATPase by suppressing the sodium pump (Patel et al 2019). In our study, preliminary data suggest that DIGI targets the L. infantum mitochondria, causing alterations in both the parasite mitochondrial membrane potential and integrity, as well as an increase in ROS production.…”

Section: Discussionmentioning

confidence: 56%

“…Thus, drug repositioning may well represent an attractive alternative, since compounds with known biological functions have been proved to be effective against parasites (Andrade-Neto et al 2018). Cardenolides are glycosides able to inhibit Na + /K + -ATPases by obstructing the Na + /K + pump mechanism (Mijatovic and Kiss 2013;Patel et al 2019). These compounds are clinically used to treat cardiac diseases, such as congestive heart failure (Gheorghiade et al 2009), and they have been reported also to possess antitumor (Slingerland et al 2013), antimalarial (Chan et al 2016), and antioxidant (Xu et al 2017) activities, among others (Eid et al 2012;Gurel et al 2017).…”

Section: Introductionmentioning

confidence: 99%

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Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis

et al. 2020

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Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC 50 and CC 50 , respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 μg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 μg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum– infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis

et al. 2020

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“…Molecular dynamics simulations were carried out in Desmond (Schrödinger Release 2019-3) package [ 48 ] with the best-scoring, top-five NPACT compounds of HE target as starting structures. We also performed simulations on the HE crystal structure in complex with 4,9- O ′-diacetyl sialic acid (cognate ligand) to utilize it as control.…”

Section: Methodsmentioning

confidence: 99%

“…Virtual screening was performed on CoV-2 HE target receptor with 1574 NPACT compounds as ligand set using YASARA Structure package (version 19.12.14; academic license). YASARA Structure implements AutoDock Vina as the dock pose search algorithm and AMBER03 force field for scoring receptor-ligand interactions [48]. Initially, the docking procedure was validated by re-docking the co-crystal ligand of HE target 4,9-O′-diacetyl sialic acid with the 20 × 20 × 20 Å grid box size (dock site) The re-docked ligand was evaluated using root mean square deviation (RMSD) measure.…”

Section: Virtual Screening Upon He Targetmentioning

confidence: 99%

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation

et al. 2020

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The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high binding affinity towards host angiotensin-converting enzyme 2 and viral hemagglutinin-acetylesterase (HE) glycoprotein receptor. We selected HE as a target in this study to identify potential inhibitors using a combination of various computational approaches such as molecular docking, ADMET analysis, dynamics simulations and binding free energy calculations. Virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin as potential HE inhibitors with better binding energy. Furthermore, molecular dynamics simulations for 100 ns time scale revealed that most of the key HE contacts were retained throughout the simulations trajectories. Binding free energy calculations using MM/PBSA approach ranked the top-five potential NPACT compounds which can act as effective HE inhibitors.

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“…Molecular docking was implemented on coronavirus hemagglutinin-esterase and 1574 NPACT compounds using YASARA software version 19.12.14 with AutoDock Vina algorithm and AMBER03 force field [40][41][42]. The docking scores were calculated using the following empirical equation:…”

Section: Molecular Dockingmentioning

confidence: 99%

Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

Patel¹,

Kumar²,

Pandya³

et al. 2020

Preprint

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The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.

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Cardiotonic steroids as potential Na⁺/K⁺-ATPase inhibitors – a computational study

Cited by 23 publications

References 41 publications

Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis

Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation

Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

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