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Mar Drugs
2021 Oct 25;1911:. doi: 10.3390/md19110604.
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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.
Zelepuga EA
,
Silchenko AS
,
Avilov SA
,
Kalinin VI
.
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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 Eupentacta fraudatrix 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 A1 (40) and A8 (44)), preceded by bonding of the glycosides with membrane sphingomyelin, phospholipids, and cholesterol. Noncovalent intermolecular interactions inside multimolecular membrane complexes and their stoichiometry differed for 40 and 44. The second mechanism was realized by cucumarioside A2 (59) 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 silicosimulations of the interactions of cucumarioside A7 (45) 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.
Figure 1. Structures of the glycosides 1–4 from Eupentacta fraudatrix.
Figure 2. Structures of the glycosides 5–15 from Massinum magnum.
Figure 3. Structures of the glycosides 16–21 from Psolus fabricii.
Figure 4. Structures of glycosides 22 and 23 from Actinocucumis typica and 24–28 from Cladolabes shcmeltzii.
Figure 5. Structures of the glycosides 29–32 from Psolus fabricii.
Figure 6. Structures of the glycosides 33–35 from Colochirus quadrangularis, 36 from Colochirus robustus and 37 from Psolus fabricii.
Figure 7. Structure of colochiroside B2 (38) from Colochirus robustus.
Figure 8. Structure of cucumarioside A3-2 from Cucumaria fallax.
Figure 9. Structures of the glycosides 40–43 from Eupentacta fraudatrix.
Figure 10. Structure of cucumarioside A8 (44) from Eupentacta fraudatrix.
Figure 11. Structures of the glycosides 45–49 from Eupentacta fraudatrix and 50 from Colochirus robustus.
Figure 12. Structures of the glycosides 51–54 from Cladolabes schmeltzii.
Figure 13. Structures of glycosides 55 and 56 from Colochirus quadrangularis and 57 and 58 from Psolus fabricii.
Figure 14. Structure of cucumariosides A1 (40), A8 (44), A7 (45), and A2 (59) used for in silico analysis of the interaction of the glycosides from the sea cucumber, Eupentacta fraudatrix, with the model membrane.
Figure 15. Spatial organization of multimolecular complex formed by two cucumarioside A1 (40) molecules (I and II) and the model membrane components. (A) 2D diagram of noncovalent intermolecular interactions of the glycoside with water-lipid environment. (B) Multimolecular complex is presented as a semitransparent molecular surface, colored according to its lipophilicity: hydrophilic areas are pink, lipophilic areas are green, the view is perpendicular to membrane surface. The molecules of solvent and some membrane components are deleted for simplicity. (C) Multimolecular complex in membrane environment, the view parallel to membrane surface. The glycoside is presented as cyan “ball” model, POPC+PSM and CHOL molecules (6 Å surrounding glycoside-lipid complex) of outer membrane leaflet are grey and light-green “ball” models, respectively; POPC+PSM and CHOL of inner membrane leaflet, distant from molecular assembly, are presented as grey and dark-green “ball and stick” models, respectively.
Figure 16. Spatial organization of multimolecular complex formed by two cucumarioside A8 (44) molecules (I and II) and the model membrane components. (A) 2D diagram of noncovalent intermolecular interactions of the glycoside with water-lipid environment. (B) Multimolecular complex is presented as a semitransparent molecular surface, colored according to its lipophilicity: hydrophilic areas are pink, lipophilic areas are green, the view is perpendicular to membrane surface. The glycoside is presented as cyan “ball” model, POPC+PSM and CHOL molecules (6 Å surrounding glycoside-lipid complex) of the outer membrane leaflet are grey and light-green “ball” models. The molecules of solvent and some membrane components are deleted for simplicity. (C) 2D diagram of noncovalent intermolecular interactions of cucumarioside A8 (44) with water-lipid environment at the initial stage of glycoside interaction with the model membrane.
Figure 17. Spatial organization of multimolecular complex formed by three molecules (I–III) of cucumarioside A2 (59) and the components of model membrane. (A) 2D diagram of intermolecular noncovalent interactions of three cucumarioside A2 (59) molecules and the components of model water/lipid bilayer environment. Hydrogen bonds are green dotted lines. (B) Front view to the cucumarioside A2 (59) multimolecular complex with a model membrane. The glycoside is presented as cyan “ball” model, POPC+PSM and CHOL (6 Å surrounding glycoside) of the outer membrane leaflet are presented as grey and light-green “ball” models, respectively; POPC+POPE and CHOL of inner membrane leaflet, distant from multimolecular assembly, are presented as grey and dark-green “ball and stick” models, respectively; CHOL molecules of the inner membrane leaflet at 5 Å distant from multimolecular complex are presented as a dark-green “ball” model. The molecules of solvent and some membrane components are deleted for simplicity.