Zelepuga EA et al. (2021), Structure-Activity Relationships of Holothuroid...

ECB-ART-50670

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.

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References [+] :

Aminin, Glycosides from edible sea cucumbers stimulate macrophages via purinergic receptors. 2016, Pubmed, Echinobase

Aminin, Glycosides from edible sea cucumbers stimulate macrophages via purinergic receptors. 2016, Pubmed , Echinobase
Aminin, Antitumor activity of the immunomodulatory lead Cumaside. 2010, Pubmed , Echinobase
Claereboudt, How different sterols contribute to saponin tolerant plasma membranes in sea cucumbers. 2018, Pubmed , Echinobase
Deleu, Complementary biophysical tools to investigate lipid specificity in the interaction between bioactive molecules and the plasma membrane: A review. 2014, Pubmed
Guan, Functional interactions between sphingolipids and sterols in biological membranes regulating cell physiology. 2009, Pubmed
Guariento, New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies. 2016, Pubmed
Kalinin, Hemolytic activities of triterpene glycosides from the holothurian order Dendrochirotida: some trends in the evolution of this group of toxins. 1996, Pubmed , Echinobase
Kalinin, System-theoretical (Holistic) approach to the modelling of structural-functional relationships of biomolecules and their evolution: an example of triterpene glycosides from sea cucumbers (Echinodermata, holothurioidea). 2000, Pubmed , Echinobase
Kersten, Liposomes and ISCOMS as vaccine formulations. 1995, Pubmed
Kim, Triterpene glycosides from sea cucumbers and their biological activities. 2012, Pubmed , Echinobase
Lee, CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. 2016, Pubmed
Lee, CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans. 2019, Pubmed
Likhatskaia, [Formation of the complex of the triterpene glycoside holothurin A with cholesterol in liposomal membranes]. 1985, Pubmed
Lin, Hemolytic mechanism of dioscin proposed by molecular dynamics simulations. 2010, Pubmed
Lorent, The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. 2014, Pubmed
Malyarenko, New Triterpene Glycosides from the Far Eastern Starfish Solaster pacificus and Their Biological Activity. 2021, Pubmed , Echinobase
Mazeĭka, [Complexation between triterpene glycosides of holothurians and cholesterol is the basis of lipid-saponin carriers of subunit protein antigens]. 2008, Pubmed , Echinobase
Mollinedo, Lipid rafts as major platforms for signaling regulation in cancer. 2015, Pubmed
Park, Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers. 2014, Pubmed , Echinobase
Rusnati, Speeding Up the Identification of Cystic Fibrosis Transmembrane Conductance Regulator-Targeted Drugs: An Approach Based on Bioinformatics Strategies and Surface Plasmon Resonance. 2018, Pubmed
Sezgin, The mystery of membrane organization: composition, regulation and roles of lipid rafts. 2017, Pubmed
Silchenko, Structures and biological activities of typicosides A1, A2, B1, C1 and C2, triterpene glycosides from the sea cucumber Actinocucumis typica. 2013, Pubmed , Echinobase
Silchenko, Colochirosides B1, B2, B3 and C, Novel Sulfated Triterpene Glycosides from the Sea Cucumber Colochirus robustus (Cucumariidae, Dendrochirotida). 2015, Pubmed , Echinobase
Silchenko, Nine New Triterpene Glycosides, Magnumosides A₁-A₄, B₁, B₂, C₁, C₂ and C₄, from the Vietnamese Sea Cucumber Neothyonidium (=Massinium) magnum: Structures and Activities against Tumor Cells Independently and in Synergy with Radioactive Irradiation. 2017, Pubmed , Echinobase
Silchenko, Structures and cytotoxic properties of cucumariosides H₂, H₃ and H₄ from the sea cucumber Eupentacta fraudatrix. 2012, Pubmed , Echinobase
Silchenko, Triterpene glycosides from the sea cucumber Eupentacta fraudatrix. Structure and biological action of cucumariosides A1, A3, A4, A5, A6, A12 and A15, seven new minor non-sulfated tetraosides and unprecedented 25-keto, 27-norholostane aglycone. 2012, Pubmed , Echinobase
Silchenko, Triterpene glycosides from the sea cucumber Eupentacta fraudatrix. Structure and cytotoxic action of cucumariosides A2, A7, A9, A10, an, A13 and A14, seven new minor non-sulfated tetraosides and an aglycone with an uncommon 18-hydroxy group. 2012, Pubmed , Echinobase
Silchenko, Structures and Bioactivities of Six New Triterpene Glycosides, Psolusosides E, F, G, H, H1, and I and the Corrected Structure of Psolusoside B from the Sea Cucumber Psolus fabricii. 2019, Pubmed , Echinobase
Silchenko, Structures and Bioactivities of Psolusosides B1, B2, J, K, L, M, N, O, P, and Q from the Sea Cucumber Psolus fabricii. The First Finding of Tetrasulfated Marine Low Molecular Weight Metabolites. 2019, Pubmed , Echinobase
Silchenko, Structures and Bioactivities of Quadrangularisosides A, A1, B, B1, B2, C, C1, D, D1-D4, and E from the Sea Cucumber Colochirus quadrangularis: The First Discovery of the Glycosides, Sulfated by C-4 of the Terminal 3-O-Methylglucose Residue. Synergetic Effect on Colony Formation of Tumor HT-29 Cells of these Glycosides with Radioactive Irradiation. 2020, Pubmed , Echinobase
Silchenko, Triterpene glycosides from the sea cucumber Eupentacta fraudatrix. Structure and biological activity of cucumariosides B1 and B2, two new minor non-sulfated unprecedented triosides. 2012, Pubmed , Echinobase
Silchenko, Structure of cucumariosides H5, H6, H7 and H8, triterpene glycosides from the sea cucumber Eupentacta fraudatrix and unprecedented aglycone with 16,22-epoxy-group. 2011, Pubmed , Echinobase
Silchenko, Structure and biological action of cladolosides B1, B2, C, C1, C2 and D, six new triterpene glycosides from the sea cucumber Cladolabes schmeltzii. 2013, Pubmed , Echinobase
Silchenko, Structures and biological activities of cladolosides C3, E1, E2, F1, F2, G, H1 and H2, eight triterpene glycosides from the sea cucumber Cladolabes schmeltzii with one known and four new carbohydrate chains. 2015, Pubmed , Echinobase
Silchenko, Cladolosides I1, I2, J1, K1, K2 and L1, monosulfated triterpene glycosides with new carbohydrate chains from the sea cucumber Cladolabes schmeltzii. 2017, Pubmed , Echinobase
Silchenko, Cladolosides C4, D1, D2, M, M1, M2, N and Q, new triterpene glycosides with diverse carbohydrate chains from sea cucumber Cladolabes schmeltzii. An uncommon 20,21,22,23,24,25,26,27-okta-nor-lanostane aglycone. The synergism of inhibitory action of non-toxic dose of the glycosides and radioactive irradiation on colony formation of HT-29 cancer cells. 2018, Pubmed , Echinobase
Silchenko, Cladolosides O, P, P1-P3 and R, triterpene glycosides with two novel types of carbohydrate chains from the sea cucumberCladolabes schmeltzii. Inhibition of cancer cells colony formation and its synergy with radioactive irradiation. 2018, Pubmed , Echinobase
Silchenko, Triterpene glycosides from the sea cucumber Eupentacta fraudatrix. Structure and biological action of cucumariosides I1, I3, I4, three new minor disulfated pentaosides. 2013, Pubmed , Echinobase
Silchenkoa, Fallaxosides C₁, C₂, D₁ and D₂, Unusual Oligosulfated Triterpene Glycosides from the Sea Cucumber Cucumariafallax (Cucumariidae, Dendrochirotida, Holothurioidea) and Taxonomic Status of this Animal. 2016, Pubmed , Echinobase
Verstraeten, The activity of the saponin ginsenoside Rh2 is enhanced by the interaction with membrane sphingomyelin but depressed by cholesterol. 2019, Pubmed

	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.