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Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies

Breast cancer is the second most common malignancy in females worldwide and poses a great challenge that necessitates the identification of novel therapeutic agents from several sources. This research aimed to study the molecular docking and molecular dynamics simulations of four proteins (such as P...

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Autores principales: Gowtham, Hittanahallikoppal Gajendramurthy, Murali, Mahadevamurthy, Singh, Sudarshana Brijesh, Shivamallu, Chandan, Pradeep, Sushma, Shivakumar, C. S., Anandan, Satish, Thampy, Anjana, Achar, Raghu Ram, Silina, Ekaterina, Stupin, Victor, Ortega-Castro, Joaquín, Frau, Juan, Flores-Holguín, Norma, Amruthesh, Kestur Nagaraj, Kollur, Shiva Prasad, Glossman-Mitnik, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536605/
https://www.ncbi.nlm.nih.gov/pubmed/36201520
http://dx.doi.org/10.1371/journal.pone.0275432
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author Gowtham, Hittanahallikoppal Gajendramurthy
Murali, Mahadevamurthy
Singh, Sudarshana Brijesh
Shivamallu, Chandan
Pradeep, Sushma
Shivakumar, C. S.
Anandan, Satish
Thampy, Anjana
Achar, Raghu Ram
Silina, Ekaterina
Stupin, Victor
Ortega-Castro, Joaquín
Frau, Juan
Flores-Holguín, Norma
Amruthesh, Kestur Nagaraj
Kollur, Shiva Prasad
Glossman-Mitnik, Daniel
author_facet Gowtham, Hittanahallikoppal Gajendramurthy
Murali, Mahadevamurthy
Singh, Sudarshana Brijesh
Shivamallu, Chandan
Pradeep, Sushma
Shivakumar, C. S.
Anandan, Satish
Thampy, Anjana
Achar, Raghu Ram
Silina, Ekaterina
Stupin, Victor
Ortega-Castro, Joaquín
Frau, Juan
Flores-Holguín, Norma
Amruthesh, Kestur Nagaraj
Kollur, Shiva Prasad
Glossman-Mitnik, Daniel
author_sort Gowtham, Hittanahallikoppal Gajendramurthy
collection PubMed
description Breast cancer is the second most common malignancy in females worldwide and poses a great challenge that necessitates the identification of novel therapeutic agents from several sources. This research aimed to study the molecular docking and molecular dynamics simulations of four proteins (such as PDB: 6CBZ, 1FDW, 5GWK and 2WTT) with the selected phytochemicals from Withania somnifera to identify the potential inhibitors for breast cancer. The molecular docking result showed that among 44 compounds, two of them, Ashwagandhanolide and Withanolide sulfoxide have the potential to inhibit estrogen receptor alpha (ERα), 17-beta-hydroxysteroid -dehydrogenase type 1 (17β-HSD1), topoisomerase II alpha (TOP2A) and p73 tetramerization domain that are expressed during breast cancer. The molecular dynamics (MD) simulations results suggested that Ashwagandhanolide remained inside the binding cavity of four targeted proteins and contributed favorably towards forming a stable protein-ligand complex throughout the simulation. Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties confirmed that Ashwagandhanolide is hydrophobic and has moderate intestinal permeability, good intestinal absorption, and poor skin permeability. The compound has a relatively low VDss value (-1.652) and can be transported across ABC transporter and good central nervous system (CNS) permeability but did not easily cross the blood-brain barrier (BBB). This compound does not possess any mutagenicity, hepatotoxicity and skin sensitization. Based on the results obtained, the present study highlights the anticancer potential of Ashwagandhanolide, a compound from W. somnifera. Furthermore, in vitro and in vivo studies are necessary to perform before clinical trials to prove the potentiality of Ashwagandhanolide.
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spelling pubmed-95366052022-10-07 Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies Gowtham, Hittanahallikoppal Gajendramurthy Murali, Mahadevamurthy Singh, Sudarshana Brijesh Shivamallu, Chandan Pradeep, Sushma Shivakumar, C. S. Anandan, Satish Thampy, Anjana Achar, Raghu Ram Silina, Ekaterina Stupin, Victor Ortega-Castro, Joaquín Frau, Juan Flores-Holguín, Norma Amruthesh, Kestur Nagaraj Kollur, Shiva Prasad Glossman-Mitnik, Daniel PLoS One Research Article Breast cancer is the second most common malignancy in females worldwide and poses a great challenge that necessitates the identification of novel therapeutic agents from several sources. This research aimed to study the molecular docking and molecular dynamics simulations of four proteins (such as PDB: 6CBZ, 1FDW, 5GWK and 2WTT) with the selected phytochemicals from Withania somnifera to identify the potential inhibitors for breast cancer. The molecular docking result showed that among 44 compounds, two of them, Ashwagandhanolide and Withanolide sulfoxide have the potential to inhibit estrogen receptor alpha (ERα), 17-beta-hydroxysteroid -dehydrogenase type 1 (17β-HSD1), topoisomerase II alpha (TOP2A) and p73 tetramerization domain that are expressed during breast cancer. The molecular dynamics (MD) simulations results suggested that Ashwagandhanolide remained inside the binding cavity of four targeted proteins and contributed favorably towards forming a stable protein-ligand complex throughout the simulation. Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties confirmed that Ashwagandhanolide is hydrophobic and has moderate intestinal permeability, good intestinal absorption, and poor skin permeability. The compound has a relatively low VDss value (-1.652) and can be transported across ABC transporter and good central nervous system (CNS) permeability but did not easily cross the blood-brain barrier (BBB). This compound does not possess any mutagenicity, hepatotoxicity and skin sensitization. Based on the results obtained, the present study highlights the anticancer potential of Ashwagandhanolide, a compound from W. somnifera. Furthermore, in vitro and in vivo studies are necessary to perform before clinical trials to prove the potentiality of Ashwagandhanolide. Public Library of Science 2022-10-06 /pmc/articles/PMC9536605/ /pubmed/36201520 http://dx.doi.org/10.1371/journal.pone.0275432 Text en © 2022 Gowtham et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gowtham, Hittanahallikoppal Gajendramurthy
Murali, Mahadevamurthy
Singh, Sudarshana Brijesh
Shivamallu, Chandan
Pradeep, Sushma
Shivakumar, C. S.
Anandan, Satish
Thampy, Anjana
Achar, Raghu Ram
Silina, Ekaterina
Stupin, Victor
Ortega-Castro, Joaquín
Frau, Juan
Flores-Holguín, Norma
Amruthesh, Kestur Nagaraj
Kollur, Shiva Prasad
Glossman-Mitnik, Daniel
Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title_full Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title_fullStr Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title_full_unstemmed Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title_short Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies
title_sort phytoconstituents of withania somnifera unveiled ashwagandhanolide as a potential drug targeting breast cancer: investigations through computational, molecular docking and conceptual dft studies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536605/
https://www.ncbi.nlm.nih.gov/pubmed/36201520
http://dx.doi.org/10.1371/journal.pone.0275432
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