Exploring the inhibitory potential of bioactive compound from Luffa acutangula against NF-κB—A molecular docking and dynamics approach

Vanajothi, Ramar; Srinivasan, Pappu

doi:10.1016/j.compbiolchem.2016.03.006

Cited by 27 publications

(7 citation statements)

References 32 publications

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“…Under normal conditions, Nrf‐2 exists in the cytoplasm by binding with its inhibitor Keap1. Once exposed to stressors or inducers, the conformation of Keap1 changes, Nrf‐2 separates from Keap1 and translocates into the nucleus to promote the expression of its downstream antioxidant genes, such as HO‐1 and NQO‐1 (Marcotte et al, ; Pang et al, ; Ramar & Pappu, ). This is consistent with our results that Nrf2 binds to Keap1 in the DMSO and the Ang II groups, whereas Sch C treatment caused remarkable separation between Keap1 and Nrf2 (Figure a).…”

Section: Discussionmentioning

confidence: 99%

“…Then, Nrf-2 separates from Keap1 and translocates into the nucleus to promote the expression of its downstream antioxidant genes [Colour figure can be viewed at wileyonlinelibrary.com] groups, whereas Sch C treatment caused remarkable separation between Keap1 and Nrf2 (Figure 4a). Previous studies indicated the potential interaction of small molecular inhibitors with the Nrf2 binding site in the Keap1 protein (Marcotte et al, 2013;Pang et al, 2016;Ramar & Pappu, 2016). To determine the potential mechanisms and target of Sch C behind this protection, we transfected RAECs with Keap1-expressing plasmids (Figure 4b).…”

Section: Endothelial Dysfunction Is the Most Common Complication Inmentioning

confidence: 99%

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Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

Han

Shi

et al. 2019

Phytotherapy Research

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Vascular endothelial dysfunction plays a crucial role in the pathogenesis of cardiovascular diseases. Oxidative stress is a key pathophysiological mechanism underpinning endothelial dysfunction. Schisandrin C (Sch C), a dibenzocyclooctadiene derivative of Schisandra chinensis, has antioxidative properties. Here, we report the use of Sch C as a novel therapeutic for the treatment of angiotensin II (Ang II)‐induced endothelial deficits and explore the underlying mechanisms and the target of Sch C. Our results demonstrated that Sch C treatment prevents aorta oxidative stress and improves relaxation in mice, challenged with subcutaneous infusion of Ang II. In addition, Sch C significantly ameliorates Ang II‐induced oxidative stress in rat aortic endothelial cells. We then discovered that these antioxidative effects of Sch C are mediated through the induction of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2). Using an expression plasmid and molecular docking, we identified that Kelch‐like ECH‐associated protein‐1 (Keap1), a negative regulator of Nrf2, is a target of Sch C. These findings provide evidence for the potential use of Sch C as an antioxidative agent for treatment of vascular endothelial deficits.

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Section: Discussionmentioning

confidence: 99%

Section: Endothelial Dysfunction Is the Most Common Complication Inmentioning

confidence: 99%

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

Han

Shi

et al. 2019

Phytotherapy Research

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“…Subsequently, the ConfGen tool was utilized to generate conformers for the ligands. Of note, Macromodel torsion angle search approach followed by minimization using OPLS-2005 force field was utilized to generate the ligand conformers [30]. This process was then followed by the pharmacophore and 3D-QSAR model generation.…”

Section: Ligand Preparationmentioning

confidence: 99%

Hyphenated 3D-QSAR statistical model-drug repurposing analysis for the identification of potent neuraminidase inhibitor

Rohini

Shanthi

2018

Cell Biochem Biophys

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The Influenza A virus is one of the principle causes of respiratory illness in human. The surface glycoprotein of the influenza virus, neuraminidase (NA), has a vital role in the release of new viral particle and spreads infection in the respiratory tract. It has been long recognized as a valid drug target for influenza A virus infection. Oseltamivir is used as a standard drug of choice for the treatment of influenza. However, the emergence of mutants with novel mutations has increased the resistance to potent NA inhibitor. In the present investigation, we have employed computer-assisted combinatorial techniques in the screening of 8621 molecules from Drug Bank to find potent NA inhibitors. A three-dimensional pharmacophore model was generated from the previously reported 28 carbocylic influenza NA inhibitors along with oseltamivir using PHASE module of Schrödinger Suite. The model generated consists of one hydrogen bond acceptor (A), one hydrogen bond donors (D), one hydrophobic group (H), and one positively charged group (P), ADHP. The hypothesis was further validated for its integrity and significance using enrichment analysis. Subsequently, an atom-based 3D-QSAR model was built using the common pharmacophore hypothesis (CPH). The developed 3D-QSAR model was found to be statistically significant with R value of 0.9866 and Q value of 0.7629. Further screening was accomplished using three-stage docking process using the Glide algorithm. The resultant lead molecules were examined for its drug-like properties using the Qikprop algorithm. Finally, the calculated pIC values of the lead compounds were validated by the AutoQSAR algorithm. Overall, the results from our analysis highlights that lisinopril (DB00722) is predicted to bind better with NA than currently approved drug. In addition, it has the best match in binding geometry conformations with the existing NA inhibitor. Note that the antiviral activity of lisinopril is reported in the literature. However, our paper is the first report on lisinopril activity against influenza A virus infection. These results are envisioned to help design the novel NA inhibitors with an increased antiviral efficacy.

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“…In addition, the Lipinski rule of five which is based on property values such as the number of hydrogen bond acceptors and donors, logP and molecular weight were also calculated to judge the overall potential of the hit molecule to qualify as a potential drug candidate. 52 Moreover, CNS activities were also predicted for the hits. The recommended range for the Central Nervous System activity is in the range of -2 (inactive) to 2 (active).…”

Section: Absorption Distribution Metabolism and Excretion (Adme)mentioning

confidence: 99%

“…50 QikProp Program of the Maestro interface was used in the prediction of both pharmaceutically pertinent properties along with the physically significant descriptors. 51 Various parameters like brain/blood partition co-efficient (QPlogBB), water solubility (QPlogS), octanol/water partition co-efficient (QPlogPo/w) and percentage of human oral absorption which are critical for the estimating the absorption and distribution of a hit compound within the body 52 were determined using this program. In addition, the Lipinski rule of five which is based on property values such as the number of hydrogen bond acceptors and donors, logP and molecular weight were also calculated to judge the overall potential of the hit molecule to qualify as a potential drug candidate.…”

Section: Absorption Distribution Metabolism and Excretion (Adme)mentioning

confidence: 99%

Exploring Novel ALK Inhibitors Using Energy Based Pharmacophore Mapping and High Throughput Virtual Screening

James¹,

Surana²,

Thigale³

et al. 2018

IJPER

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Introduction: Recent years has witnessed major paradigm shifts in the treatment of NSCLC with the emergence of biomarkers and targeted therapies. Most importantly, ALK is a validated biomarker and its inhibition using targeted therapies have had significant effects on patients suffering from NSCLC. However, emergence of drug resistance has limited the usage of these agents in the patients. Objective: In the present objective, e-pharmacophore based virtual screening was employed to discover potent ALK inhibitors from a natural compound database, TIPdb. Result: Screening of TIPdb using the e-pharmacophore model (DDRRR) retrieved 1000 hits. The docking procedures and ADME analysis led to the identification of piperphilippinin VI as the best hit. Further interaction analysis showed that piperphilippinin VI exhibited crucial interactions with kinase domain of the protein, which is the major targeting site for ALK inhibitors. Note that, PASS prediction analysis highlighted the presence of anti-neoplastic activity of the hit molecule towards lung cancer in particular NSCLC. Conclusion: The comprehensive analysis of the present study shows that, piperphilippinin VI has higher binding affinity, low toxicity profiles and increased CNS activity. We believe that these observations are of immense importance in the rational designing of a novel and potent ALK inhibitors from natural sources.

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Exploring the inhibitory potential of bioactive compound from Luffa acutangula against NF-κB—A molecular docking and dynamics approach

Cited by 27 publications

References 32 publications

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

Hyphenated 3D-QSAR statistical model-drug repurposing analysis for the identification of potent neuraminidase inhibitor

Exploring Novel ALK Inhibitors Using Energy Based Pharmacophore Mapping and High Throughput Virtual Screening

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