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In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer

[Image: see text] Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is “t...

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Autores principales: Singh, Vishal, Verma, Suman, Fatima, Fiza, Samanta, Sintu Kumar, Varadwaj, Pritish Kumar, Sahoo, Amaresh Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10586293/
https://www.ncbi.nlm.nih.gov/pubmed/37867720
http://dx.doi.org/10.1021/acsomega.3c03640
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author Singh, Vishal
Verma, Suman
Fatima, Fiza
Samanta, Sintu Kumar
Varadwaj, Pritish Kumar
Sahoo, Amaresh Kumar
author_facet Singh, Vishal
Verma, Suman
Fatima, Fiza
Samanta, Sintu Kumar
Varadwaj, Pritish Kumar
Sahoo, Amaresh Kumar
author_sort Singh, Vishal
collection PubMed
description [Image: see text] Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is “turn-on”. Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via in silico screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer.
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spelling pubmed-105862932023-10-20 In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer Singh, Vishal Verma, Suman Fatima, Fiza Samanta, Sintu Kumar Varadwaj, Pritish Kumar Sahoo, Amaresh Kumar ACS Omega [Image: see text] Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is “turn-on”. Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via in silico screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer. American Chemical Society 2023-10-03 /pmc/articles/PMC10586293/ /pubmed/37867720 http://dx.doi.org/10.1021/acsomega.3c03640 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Singh, Vishal
Verma, Suman
Fatima, Fiza
Samanta, Sintu Kumar
Varadwaj, Pritish Kumar
Sahoo, Amaresh Kumar
In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title_full In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title_fullStr In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title_full_unstemmed In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title_short In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer
title_sort in silico study of a small bioactive molecule targeting topoisomerase ii and p53-mdm2 complex in triple-negative breast cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10586293/
https://www.ncbi.nlm.nih.gov/pubmed/37867720
http://dx.doi.org/10.1021/acsomega.3c03640
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