Computational Insights into the Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl Ester for Treatment of Aberrant-EGFR Driven Lung Cancers

Malik, Vidhi; Kumar, Vipul; Kaul, Sunil C.; Wadhwa, Renu; Sundar, Durai

doi:10.3390/biom11020160

Cited by 15 publications

(12 citation statements)

References 80 publications

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“…The potential of CAPE, Wi-A and Wi-N to serve as ATP competitive inhibitors of BRAF WT and BRAF V600E mutant activity was explored in this study. The method used here is similar to our previously published study ( Malik et al., 2021 ). Crystal structure of active conformation of BRAF WT (extracted from BRAF-MEK1 dimer (PDB ID: 4MNE )) and BRAF V600E (PDB ID: 6P7G ) were obtained from Protein Data Bank ( Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The results showed EGFR, ABL and BRAF were among the top hits and indicated that these compounds could serve as a dual inhibitor of EGFR and BRAF like BGB283. In a recently published study, we reported that these molecules might serve as ATP competitive inhibitors against various EGFR mutants, including exon 20 insertion mutations of EGFR ( Malik et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Malik

Kumar

Kaul

et al. 2021

Current Research in Structural Biology

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Serine/threonine-protein kinase B-raf (BRAF) plays a significant role in regulating cell division and proliferation through MAPK/ERK pathway. The constitutive expression of wild-type BRAF (BRAF WT ) and its mutant forms, especially V600E (BRAF V600E ), has been linked to multiple cancers. Various synthetic drugs have been approved and are in clinical trials, but most of them are reported to become ineffective within a short duration. Therefore, combinational therapy involving multiple drugs are often recruited for cancer treatment. However, they lead to toxicity and adverse side effects. In this computational study, we have investigated three natural compounds, namely Withaferin-A (Wi-A), Withanone (Wi-N) and Caffeic Acid Phenethyl ester (CAPE) for anti-BRAF WT and anti-BRAF V600E activity. We found that these compounds could bind stably at ATP-binding site in both BRAF WT and BRAF V600E proteins. In-depth analysis revealed that these compounds maintained the active conformation of wild-type BRAF protein by inducing αC-helix-In, DFG-In, extended activation segment and well-aligned R-spine residues similar to already known drugs Vemurafenib (VEM), BGB283 and Ponatinib. In terms of binding energy, among the natural compounds, CAPE showed better affinity towards both wild-type and V600E mutant proteins than the other two compounds. These data suggested that CAPE, Wi-A and Wi-N have potential to block constitutive autophosphorylation of BRAF and hence warrant in vitro and in vivo experimental validation.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Malik

Kumar

Kaul

et al. 2021

Current Research in Structural Biology

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“…The best-docked poses of the protein–ligand complexes were further taken for molecular dynamics (MD) simulations using Desmond from the Schrodinger suite [ 36 ]. The MD simulation protocol used here has been described in detail in our previous study [ 43 ]. Each of the protein–ligand systems was solvated in TIP3P water model.…”

Section: Methodsmentioning

confidence: 99%

Computational and in vitro experimental analyses of the anti-COVID-19 potential of Mortaparib and MortaparibPlus

et al. 2021

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Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30–60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.

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“…The best-docked poses of the protein-ligand complexes were further taken for MD simulations using Desmond from the Schrodinger suite (36). The MD simulation protocol used here has been described in detail in our previous study (43). Each of the protein-ligand systems was solvated in TIP3P water model.…”

Section: Molecular Dynamics (Md) Simulations Of the Docked Systemsmentioning

confidence: 99%

Computational and in vitro experimental analyses of the Anti-COVID-19 potential of Mortaparib and MortaparibPlus

et al. 2021

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View full text Add to dashboard Cite

COVID-19 pandemic caused by SARS-CoV-2 virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compound/s that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (Angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to downregulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused downregulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell based anti-virus drug screening assay showed 30~60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggests that these two closely related compounds possess multimodal anti-COVID 19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.

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Computational Insights into the Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl Ester for Treatment of Aberrant-EGFR Driven Lung Cancers

Cited by 15 publications

References 80 publications

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Computational and in vitro experimental analyses of the anti-COVID-19 potential of Mortaparib and MortaparibPlus

Computational and in vitro experimental analyses of the Anti-COVID-19 potential of Mortaparib and MortaparibPlus

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