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

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 (BRAFWT) and its mutant forms, especially V600E (BRAFV600E), has been linked to multiple cancers. Various synthe...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Vidhi Malik, Vipul Kumar, Sunil C. Kaul, Renu Wadhwa, Durai Sundar
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	BRAF BRAF V600E mutant Withaferin-A Withanone Caffeic acid phenethyl ester ATP-Competitive inhibitors and cancer Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/800b2c180bcf41c1b35c62eda2e38431
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:800b2c180bcf41c1b35c62eda2e38431
record_format	dspace
spelling	oai:doaj.org-article:800b2c180bcf41c1b35c62eda2e384312021-11-28T04:38:14ZPotential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study2665-928X10.1016/j.crstbi.2021.11.004https://doaj.org/article/800b2c180bcf41c1b35c62eda2e384312021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2665928X21000271https://doaj.org/toc/2665-928XSerine/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 (BRAFWT) and its mutant forms, especially V600E (BRAFV600E), 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-BRAFWT and anti-BRAFV600E activity. We found that these compounds could bind stably at ATP-binding site in both BRAFWT and BRAFV600E 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.Vidhi MalikVipul KumarSunil C. KaulRenu WadhwaDurai SundarElsevierarticleBRAFBRAF V600E mutantWithaferin-AWithanoneCaffeic acid phenethyl esterATP-Competitive inhibitors and cancerBiology (General)QH301-705.5ENCurrent Research in Structural Biology, Vol 3, Iss , Pp 301-311 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BRAF BRAF V600E mutant Withaferin-A Withanone Caffeic acid phenethyl ester ATP-Competitive inhibitors and cancer Biology (General) QH301-705.5
spellingShingle	BRAF BRAF V600E mutant Withaferin-A Withanone Caffeic acid phenethyl ester ATP-Competitive inhibitors and cancer Biology (General) QH301-705.5 Vidhi Malik Vipul Kumar Sunil C. Kaul Renu Wadhwa Durai Sundar Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
description	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 (BRAFWT) and its mutant forms, especially V600E (BRAFV600E), 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-BRAFWT and anti-BRAFV600E activity. We found that these compounds could bind stably at ATP-binding site in both BRAFWT and BRAFV600E 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.
format	article
author	Vidhi Malik Vipul Kumar Sunil C. Kaul Renu Wadhwa Durai Sundar
author_facet	Vidhi Malik Vipul Kumar Sunil C. Kaul Renu Wadhwa Durai Sundar
author_sort	Vidhi Malik
title	Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
title_short	Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
title_full	Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
title_fullStr	Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
title_full_unstemmed	Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study
title_sort	potential of withaferin-a, withanone and caffeic acid phenethyl ester as atp-competitive inhibitors of braf: a bioinformatics study
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/800b2c180bcf41c1b35c62eda2e38431
work_keys_str_mv	AT vidhimalik potentialofwithaferinawithanoneandcaffeicacidphenethylesterasatpcompetitiveinhibitorsofbrafabioinformaticsstudy AT vipulkumar potentialofwithaferinawithanoneandcaffeicacidphenethylesterasatpcompetitiveinhibitorsofbrafabioinformaticsstudy AT sunilckaul potentialofwithaferinawithanoneandcaffeicacidphenethylesterasatpcompetitiveinhibitorsofbrafabioinformaticsstudy AT renuwadhwa potentialofwithaferinawithanoneandcaffeicacidphenethylesterasatpcompetitiveinhibitorsofbrafabioinformaticsstudy AT duraisundar potentialofwithaferinawithanoneandcaffeicacidphenethylesterasatpcompetitiveinhibitorsofbrafabioinformaticsstudy
_version_	1718408269321469952

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

Ejemplares similares