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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1660-3397/19/11/604 |
| _version_ | 1797509556254801920 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:19:26Z |
| format | Article |
| id | doaj.art-1450beb8dfc34cc1b6dae325f016ed29 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T05:19:26Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-1450beb8dfc34cc1b6dae325f016ed292023-11-23T00:07:08ZengMDPI AGMarine Drugs1660-33972021-10-01191160410.3390/md19110604Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic ActionElena A. Zelepuga0Alexandra S. Silchenko1Sergey A. Avilov2Vladimir I. Kalinin3G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022 Vladivostok, RussiaG.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022 Vladivostok, RussiaG.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022 Vladivostok, RussiaG.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022 Vladivostok, RussiaThe 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.https://www.mdpi.com/1660-3397/19/11/604triterpene glycosidessea cucumbermembranolytic actionhemolyticcytotoxic activitymolecular dynamic simulation |
| spellingShingle | 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 Marine Drugs triterpene glycosides sea cucumber membranolytic action hemolytic cytotoxic activity molecular dynamic simulation |
| 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_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_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_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 |
| topic | triterpene glycosides sea cucumber membranolytic action hemolytic cytotoxic activity molecular dynamic simulation |
| url | https://www.mdpi.com/1660-3397/19/11/604 |
| work_keys_str_mv | AT elenaazelepuga structureactivityrelationshipsofholothuroidstriterpeneglycosidesandsomeinsilicoinsightsobtainedbymoleculardynamicsstudyonthemechanismsoftheirmembranolyticaction AT alexandrassilchenko structureactivityrelationshipsofholothuroidstriterpeneglycosidesandsomeinsilicoinsightsobtainedbymoleculardynamicsstudyonthemechanismsoftheirmembranolyticaction AT sergeyaavilov structureactivityrelationshipsofholothuroidstriterpeneglycosidesandsomeinsilicoinsightsobtainedbymoleculardynamicsstudyonthemechanismsoftheirmembranolyticaction AT vladimirikalinin structureactivityrelationshipsofholothuroidstriterpeneglycosidesandsomeinsilicoinsightsobtainedbymoleculardynamicsstudyonthemechanismsoftheirmembranolyticaction |