Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane

Abstract Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that hav...

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Autores principales:	Renu Wadhwa, Neetu Singh Yadav, Shashank P. Katiyar, Tomoko Yaguchi, Chohee Lee, Hyomin Ahn, Chae-Ok Yun, Sunil C. Kaul, Durai Sundar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/290ac1e53745458f8bf77d2bdd372a0e
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spelling	oai:doaj.org-article:290ac1e53745458f8bf77d2bdd372a0e2021-12-02T13:57:26ZMolecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane10.1038/s41598-021-81729-z2045-2322https://doaj.org/article/290ac1e53745458f8bf77d2bdd372a0e2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81729-zhttps://doaj.org/toc/2045-2322Abstract Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.Renu WadhwaNeetu Singh YadavShashank P. KatiyarTomoko YaguchiChohee LeeHyomin AhnChae-Ok YunSunil C. KaulDurai SundarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Renu Wadhwa Neetu Singh Yadav Shashank P. Katiyar Tomoko Yaguchi Chohee Lee Hyomin Ahn Chae-Ok Yun Sunil C. Kaul Durai Sundar Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
description	Abstract Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.
format	article
author	Renu Wadhwa Neetu Singh Yadav Shashank P. Katiyar Tomoko Yaguchi Chohee Lee Hyomin Ahn Chae-Ok Yun Sunil C. Kaul Durai Sundar
author_facet	Renu Wadhwa Neetu Singh Yadav Shashank P. Katiyar Tomoko Yaguchi Chohee Lee Hyomin Ahn Chae-Ok Yun Sunil C. Kaul Durai Sundar
author_sort	Renu Wadhwa
title	Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
title_short	Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
title_full	Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
title_fullStr	Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
title_full_unstemmed	Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane
title_sort	molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-a and withanone across the model cell membrane
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/290ac1e53745458f8bf77d2bdd372a0e
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Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane

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