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Sci. Pharm. 2018, 86(3), 32; https://doi.org/10.3390/scipharm86030032

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

1
The United Graduate School of Agricultural Sciences, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan
2
PAK Research Center, University of the Ryukyus, Okinawa 903-0213, Japan
3
Department of Bioscience and Biotechnology, Faculty of Agriculture, University of the Ryukyus, Senbaru 1, Nishihara-cho, Okinawa 903-0213, Japan
4
Division of Computer Aided Drug Design, The Red-Green Research Centre, 218 Elephant Road, Dhaka 1205, Bangladesh
5
Subtropical Field Science Center, University of the Ryukyus, Senbaru 1, Nishihara-cho, Okinawa 903-0213, Japan
*
Authors to whom correspondence should be addressed.
Received: 3 July 2018 / Revised: 23 August 2018 / Accepted: 23 August 2018 / Published: 31 August 2018
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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 IC50 values of 0.5–2.5 µM, and on brine shrimps with an IC50 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. View Full-Text
Keywords: Holothuria atra; desulfated echinoside B; molecular docking; molecular dynamics; p21-activated kinase 1 Holothuria atra; desulfated echinoside B; molecular docking; molecular dynamics; p21-activated kinase 1
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Shahinozzaman, M.; Ishii, T.; Takano, R.; Halim, M.A.; Hossain, M.A.; Tawata, S. 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. Sci. Pharm. 2018, 86, 32.

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