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

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.

Structures and Biologic Activity of Chitonoidosides I, J, K, K1 and L-Triterpene Di-, Tri- and Tetrasulfated Hexaosides from the Sea Cucumber Psolus chitonoides

“…Chitonoidosides I (1) and J (2), di-and trisulfated hexaosides, correspondingly, with a xylose residue in the bottom semi-chain demonstrated lower cytotoxicity in comparison with chitonoidosides K (3) and L (5) having four sulfate groups and glucose residue in the bottom semi-chain. Chitonoidoside K 1 (4) was expectedly inactive in all experiments due to the presence of a hydroxyl group in the aglycone side chain [10,22].…”

“…The history of investigation of chemical structures [1][2][3][4][5], biological activities [6][7][8][9][10][11], evolution [2,[12][13][14], taxonomic specificity of triterpene glycosides from the sea cucumbers [2,3,[15][16][17], their biosynthesis [18,19], ecological role and functions [8,20] as well as structure-activity relationships [21,22] is rather long. However, the recent researches demonstrate the further perspectives in this field due to the finding of new unusual structures, the deepening of understanding of biosynthetic process leading to the glycosides and the appearance of the other aspects concerning their origin and properties, including the modelling in silico mechanisms of interaction of the glycosides with biological targets [22].…”

Microwave-Assisted Desulfation of the Hemolytic Saponins Extracted from Holothuria scabra Viscera

“…As the membrane concentration of these complexes increases, aggregation phenomena occur on the way to the pore formation, ultimately inducing membrane permeabilization and cell death. The saponin-biological membrane interaction is directly dependent on the structure of the saponins [25,26], as also theoretically demonstrated using computational chemistry [28,29]. Establishing the Structure-Activity Relationship (SAR) of saponins represents a challenging task due to their high structural diversity and the variety of biological activities they are associated with in their ecosystems [23].…”

Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides: Chemical Structures and Cytotoxicities of Chitonoidosides E1, F, G, and H

“…Extensive studies on glycosides provide significant information on the exploration of chemical diversity, properties and biological activity of a huge collection of natural products, which are a valuable and promising resource of new drugs and medicines [1][2][3][4][5][6][7][8]. The interest in these compounds is also driven by their taxonomic specificity [9][10][11] as well as the possibility of reconstructing the sequences of the biosynthetic transformations of aglycones and carbohydrate chains during biosynthesis [12,13] and of defining the peculiarities of «structure-activity relationships» based on knowledge about their structural diversity [14]. All this indicates the relevance of searching for new glycosides.…”