scholarly journals 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 ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. 604
Author(s):  
Elena A. Zelepuga ◽  
Alexandra S. Silchenko ◽  
Sergey A. Avilov ◽  
Vladimir I. Kalinin
Keyword(s):  
Molecular Dynamics ◽  
Hemolytic Activity ◽  
In Silico ◽  
Sea Cucumber ◽  
Hydrophobic Interactions ◽  
Membrane Surface ◽  
Erythrocyte Membranes ◽  
Inner Membrane ◽  
Structure Activity Relationships ◽  
Structure Activity

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.

scholarly journals Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

2013 ◽  
Vol 14 (1) ◽  
pp. 1293-1309 ◽  
Author(s):  
Rodrigo de Araújo ◽  
Felipe Guerra ◽  
Edeltrudes de O. Lima ◽  
Carlos de Simone ◽  
Josean Tavares ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
In Silico ◽  
Coumarin Derivatives ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
In Silico Studies

scholarly journals In Silico and In Vitro Structure–Activity Relationship of Mastoparan and Its Analogs

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 561
Author(s):  
Prapenpuksiri Rungsa ◽  
Steve Peigneur ◽  
Nisachon Jangpromma ◽  
Sompong Klaynongsruang ◽  
Jan Tytgat ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Biological Activity ◽  
Hemolytic Activity ◽  
In Silico ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Helical Conformation ◽  
Structure Activity ◽  
Wide Range ◽  
Α Helix

Antimicrobial peptides are an important class of therapeutic agent used against a wide range of pathogens such as Gram-negative and Gram-positive bacteria, fungi, and viruses. Mastoparan (MpVT) is an α-helix and amphipathic tetradecapeptide obtained from Vespa tropica venom. This peptide exhibits antibacterial activity. In this work, we investigate the effect of amino acid substitutions and deletion of the first three C-terminal residues on the structure–activity relationship. In this in silico study, the predicted structure of MpVT and its analog have characteristic features of linear cationic peptides rich in hydrophobic and basic amino acids without disulfide bonds. The secondary structure and the biological activity of six designed analogs are studied. The biological activity assays show that the substitution of phenylalanine (MpVT1) results in a higher antibacterial activity than that of MpVT without increasing toxicity. The analogs with the first three deleted C-terminal residues showed decreased antibacterial and hemolytic activity. The CD (circular dichroism) spectra of these peptides show a high content α-helical conformation in the presence of 40% 2,2,2- trifluoroethanol (TFE). In conclusion, the first three C-terminal deletions reduced the length of the α-helix, explaining the decreased biological activity. MpVTs show that the hemolytic activity of mastoparan is correlated to mean hydrophobicity and mean hydrophobic moment. The position and spatial arrangement of specific hydrophobic residues on the non-polar face of α-helical AMPs may be crucial for the interaction of AMPs with cell membranes.

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