Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action

The article describes the structure-activity relationships (SAR) for a broad series of sea cucumber glycosides on different tumor cell lines and erythrocytes, and an in silico modulation of the interaction of selected glycosides from the sea cucumber <em>Eupentacta fraudatrix</em> with m...

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Autores principales:	Elena A. Zelepuga, Alexandra S. Silchenko, Sergey A. Avilov, Vladimir I. Kalinin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	triterpene glycosides sea cucumber membranolytic action hemolytic cytotoxic activity molecular dynamic simulation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1450beb8dfc34cc1b6dae325f016ed29
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spelling	oai:doaj.org-article:1450beb8dfc34cc1b6dae325f016ed292021-11-25T18:12:45ZStructure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action10.3390/md191106041660-3397https://doaj.org/article/1450beb8dfc34cc1b6dae325f016ed292021-10-01T00:00:00Zhttps://www.mdpi.com/1660-3397/19/11/604https://doaj.org/toc/1660-3397The article describes the structure-activity relationships (SAR) for a broad series of sea cucumber glycosides on different tumor cell lines and erythrocytes, and an in silico modulation of the interaction of selected glycosides from the sea cucumber <em>Eupentacta fraudatrix</em> with model erythrocyte membranes using full-atom molecular dynamics (MD) simulations. The in silico approach revealed that the glycosides bound to the membrane surface mainly through hydrophobic interactions and hydrogen bonds. The mode of such interactions depends on the aglycone structure, including the side chain structural peculiarities, and varies to a great extent. Two different mechanisms of glycoside/membrane interactions were discovered. The first one was realized through the pore formation (by cucumariosides A<sub>1</sub> (<strong>40</strong>) and A<sub>8</sub> (<strong>44</strong>)), preceded by bonding of the glycosides with membrane sphingomyelin, phospholipids, and cholesterol. Noncovalent intermolecular interactions inside multimolecular membrane complexes and their stoichiometry differed for <strong>40</strong> and <strong>44.</strong> The second mechanism was realized by cucumarioside A<sub>2</sub> (<b>59</b>) through the formation of phospholipid and cholesterol clusters in the outer and inner membrane leaflets, correspondingly. Noticeably, the glycoside/phospholipid interactions were more favorable compared to the glycoside/cholesterol interactions, but the glycoside possessed an agglomerating action towards the cholesterol molecules from the inner membrane leaflet. In silico<i> </i>simulations of the interactions of cucumarioside A<sub>7</sub> (<b>45</b>) with model membrane demonstrated only slight interactions with phospholipid polar heads and the absence of glycoside/cholesterol interactions. This fact correlated well with very low experimental hemolytic activity of this substance. The observed peculiarities of membranotropic action are in good agreement with the corresponding experimental data on hemolytic activity of the investigated compounds in vitro.Elena A. ZelepugaAlexandra S. SilchenkoSergey A. AvilovVladimir I. KalininMDPI AGarticletriterpene glycosidessea cucumbermembranolytic actionhemolyticcytotoxic activitymolecular dynamic simulationBiology (General)QH301-705.5ENMarine Drugs, Vol 19, Iss 604, p 604 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	triterpene glycosides sea cucumber membranolytic action hemolytic cytotoxic activity molecular dynamic simulation Biology (General) QH301-705.5
spellingShingle	triterpene glycosides sea cucumber membranolytic action hemolytic cytotoxic activity molecular dynamic simulation Biology (General) QH301-705.5 Elena A. Zelepuga Alexandra S. Silchenko Sergey A. Avilov Vladimir I. Kalinin Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
description	The article describes the structure-activity relationships (SAR) for a broad series of sea cucumber glycosides on different tumor cell lines and erythrocytes, and an in silico modulation of the interaction of selected glycosides from the sea cucumber <em>Eupentacta fraudatrix</em> with model erythrocyte membranes using full-atom molecular dynamics (MD) simulations. The in silico approach revealed that the glycosides bound to the membrane surface mainly through hydrophobic interactions and hydrogen bonds. The mode of such interactions depends on the aglycone structure, including the side chain structural peculiarities, and varies to a great extent. Two different mechanisms of glycoside/membrane interactions were discovered. The first one was realized through the pore formation (by cucumariosides A<sub>1</sub> (<strong>40</strong>) and A<sub>8</sub> (<strong>44</strong>)), preceded by bonding of the glycosides with membrane sphingomyelin, phospholipids, and cholesterol. Noncovalent intermolecular interactions inside multimolecular membrane complexes and their stoichiometry differed for <strong>40</strong> and <strong>44.</strong> The second mechanism was realized by cucumarioside A<sub>2</sub> (<b>59</b>) through the formation of phospholipid and cholesterol clusters in the outer and inner membrane leaflets, correspondingly. Noticeably, the glycoside/phospholipid interactions were more favorable compared to the glycoside/cholesterol interactions, but the glycoside possessed an agglomerating action towards the cholesterol molecules from the inner membrane leaflet. In silico<i> </i>simulations of the interactions of cucumarioside A<sub>7</sub> (<b>45</b>) with model membrane demonstrated only slight interactions with phospholipid polar heads and the absence of glycoside/cholesterol interactions. This fact correlated well with very low experimental hemolytic activity of this substance. The observed peculiarities of membranotropic action are in good agreement with the corresponding experimental data on hemolytic activity of the investigated compounds in vitro.
format	article
author	Elena A. Zelepuga Alexandra S. Silchenko Sergey A. Avilov Vladimir I. Kalinin
author_facet	Elena A. Zelepuga Alexandra S. Silchenko Sergey A. Avilov Vladimir I. Kalinin
author_sort	Elena A. Zelepuga
title	Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
title_short	Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
title_full	Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
title_fullStr	Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
title_full_unstemmed	Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action
title_sort	structure-activity relationships of holothuroid’s triterpene glycosides and some in silico insights obtained by molecular dynamics study on the mechanisms of their membranolytic action
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1450beb8dfc34cc1b6dae325f016ed29
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Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action

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