Abstract
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 silico simulations 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.
Highlights
The triterpene glycosides of sea cucumbers are natural compounds that have of sea cucumbers are natural compounds thatbeen have been investigated for time
The influence of sulfate groups on the membranotropic action of the glycosides depends on the architecture of the sugar chain and the positions of sulfate groups
The structure-activity relationships (SAR) for the sea cucumber triterpene glycosides illustrated by their action on mouse erythrocytes, is very complicated
Summary
The selective bonding to the sterols of the cell membranes underlines the molecular mechanisms of action of many natural toxins, including triterpene glycosides of the sea cucumbers. The saturation of ascites cell membranes with cholesterol increased the cytotoxicity of the sea cucumber glycosides [9]. The authors showed that the addition of cholesterol to corresponding tumor cell culture media significantly decreases the cytotoxicity of these glycosides. It clearly confirmed the cholesterol-dependent character of the membranolytic action of sea cucumber triterpene glycosides. It is of special interest that the activity of a glycoside with
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