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Title :Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study
Authors :Shahinozzaman, Md
Ishii, Takahiro
Takano, Ryo
Halim, Mohammad A.
Hossain, Amzad Md
Tawata, Shinkichi
Issue Date :31-Aug-2018
Abstract :Sea cucumbers have long been utilized in foods and Asiatic folk medicines for their nutritive and health benefits. Herein, three sea cucumber species were investigated and Holothuria atra showed the highest cytotoxicity among these. Next, a desulfated saponin, desulfated echinoside B (DEB), was purified from H. atra through bioassay-guided fractionation. LC-ESI-MS (Liquid chromatography-electrospray ionization mass spectrometry) analysis also showed H. atra to be a rich source of saponins. DEB showed cytotoxicity on cancer cells with IC_50 values of 0.5–2.5 μM, and brine shrimps with an IC_50 value of 9.2 μM. In molecular docking studies, DEB was found to bind strongly with the catalytic domain of PAK1 (p21-activated kinase 1) and it showed binding energy of ―8.2 kcal/mol compared to binding energy of ―7.7 kcal/mol for frondoside A (FRA). Both of them bind to the novel allosteric site close to the ATP-binding cleft. Molecular dynamics (MD) simulation demonstrated that DEB can form a more stable complex with PAK1, remaining inside the allosteric binding pocket and forming the maximum number of hydrogen bonds with the surrounding residues. Moreover, important ligand binding residues were found to be less fluctuating in the DEB-PAK1 complex than in the FRA-PAK1 complex throughout MD simulation. Our experimental and computational studies showed that both DEB and FRA can act as natural allosteric PAK1 inhibitors and DEB appeared to be more promising than FRA.
URL :https://doi.org/10.3390/scipharm86030032
Type Local :雑誌掲載論文
ISSN :2218-0532
Publisher :MDPI
URI :http://hdl.handle.net/20.500.12000/44785
Citation :Scientia Pharmaceutica Vol.86 no.3 p.1 -13
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Agriculture)

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