MOLECULAR DOCKING OF HYRTIMOMINE A-K FROM MARINE SPONGE HYRTIOS SPP. AS ANTICANCER TARGET OF PHOSPHOINOSITIDE-DEPENDENT KINASE 1

  • RAMA ADIGA Division of Bioinformatics and Computational Genomics, Nitte University Centre for Science Education and Research, Nitte Deemed to be University, Paneer Campus, Mangalore, Karnataka, India.

Abstract

Objective: The hyrtimomine A-K class of indole-based compounds extracted from Hyrtios spp. of sponges from the sea has not been studied for their anticancer properties. Phosphoinositide-dependent kinase 1 (PDK1) is a master regulator of many types of cancer. Compounds currently targeting PDK1 are currently of poor specificity and solubility. Hence, molecular docking to look for new compounds inhibiting PDK1 from the marine environment was carried out.


Methods: Target selection for ligands hyrtimomine A-K was done using PharmMapper tool. Molecular docking was done using iGEMDOCK 2.1, a generic evolutionary method of docking. Site moiety mapping was done in SimMap to extract the anchor preference of the top hits. Comparison of ligand binding energies, pharmacokinetic properties with lead compound BX-517 was carried out.


Results: Hyrtimomine B, C, D, and G were top hits using iGEMDOCK. The highest score was obtained for hyrtimomine C. Van der Waals interaction at T222 and V96 and hydrogen bond interaction at K111 determined pocket stability. The solubility properties of the compound showed higher score for hyrtimomine C. The conserved features of hyrtimomine C were then compared with the crystal structure of lead compound (BX-517, which was not developed further due to poor solubility and bioavailability). The pharmacokinetic properties of hyrtimomine C were superior to BX-517 and had better solubility and drug-likeness score, hence, may be a candidate structure for drug development.


Conclusion: The unique azapeno indole structure of hyrtimomine C highlighted the mode of binding and residues in binding site.

Keywords: GEMDOCK,, Hyrtimomine,, Phosphoinositide-dependent kinase 1,, Cancer,, Metastasis,, Hyrtios,, Indole., SimMap,

References

1. Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM, et al. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem J 2003;375:531-8.
2. Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J 2001;20:4380-90.
3. Leroux AE, Schulze JO, Biondi RM. AGC kinases, mechanisms of regulation and innovative drug development. Semin Cancer Biol 2018;48:1-7.
4. Gagliardi PA, di Blasio L, Puliafito A, Seano G, Sessa R, Chianale F, et al. PDK1-mediated activation of MRCK? regulates directional cell migration and lamellipodia retraction. J Cell Biol 2014;206:415-34.
5. Pinner S, Sahai E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol 2008;10:127-37.
6. Peifer C, Alessi DR. Small-molecule inhibitors of PDK1. ChemMedChem 2008;3:1810-38.
7. Naymagon L, Abdul-Hay M. Novel agents in the treatment of multiple myeloma: A review about the future. J Hematol Oncol 2016;9:52.
8. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 2005;280:19867-74.
9. Keane NA, Glavey SV, Krawczyk J, O’Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets 2014;18:897 915.
10. Yang C, Huang X, Liu H, Xiao F, Wei J, You L, et al. PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242. Oncotarget 2017;8:39185-97.
11. Mora A, Komander D, van Aalten DM, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 2004;15:161-70.
12. Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, et al. Genetic and pharmacological inhibition of PDK1 in cancer cells: Characterization of a selective allosteric kinase inhibitor. J Biol Chem 2011;286:6433-48.
13. Wucherer-Plietker M, Merkul E, Müller TJJ, Esdar C, Knöchel T, Heinrich T, et al. Discovery of novel 7-azaindoles as PDK1 inhibitors. Bioorg Med Chem Lett 2016;26:3073-80.
14. Salucci S, Burattini S, Buontempo F, Orsini E, Furiassi L, Mari M, et al. Marine bisindole alkaloid: A potential apoptotic inducer in human cancer cells. Eur J Histochem 2018;62:2881.
15. Nesi G, Sestito S, Mey V, Ricciardi S, Falasca M, Danesi R, et al. Synthesis of novel 3,5-disubstituted-2-oxindole derivatives as antitumor agents against human nonsmall cell lung cancer. ACS Med Chem Lett 2013;4:1137-41.
16. Sestito S, Nesi G, Daniele S, Martelli A, Digiacomo M, Borghini A, et al. Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme. Eur J Med Chem 2015;105:274-88.
17. Jain M, Modi M, Agarwal M, Sharma H. Synthesis, free radical scavenging and DNA cleavage activities of some novel indole derivatives. Int J Pharm Pharm Sci 2015;7:97-103.
18. Rathod AS, Godipurge SS, Biradar JS. Synthesis of indole, coumarinyl and pyridinyl derivatives of isoniazid as potent antitubercular and antimicrobial agents and their molecular docking studies. Int J Pharm Pharm Sci 2017;9:233-40.
19. Momose R, Tanaka N, Fromont J, Kobayashi J. Hyrtimomines A-C, new heteroaromatic alkaloids from a sponge Hyrtios sp. Org Lett 2013;15:2010-3.
20. Tanaka N, Momose R, Nakaguchi TA, Gonoi T, Fromont J, Kobayashi J. Hyrtimomines, indole alkaloids from Okinawan marine sponges Hyrtios spp. Tetrahedron 2014;70:832-7.
21. Shady NH, Hossary EE, Fouad MA, Gulder TA, Kamel MS, Abdelmohsen UR. Bioactive natural products of marine sponges from the genus Hyrtios. Molecules 2017;22:781-802.
22. Liu X, Ouyang S, Yu B, Liu Y, Huang K, Gong J, et al. PharmMapper server: A web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res 2010;38:W609 14.
23. Yang JM, Chen CC. GEMDOCK: A generic evolutionary method for molecular docking. Proteins 2004;55:288-304.
24. Chen YF, Hsu KC, Lin SR, Wang WC, Huang YC, Yang JM, et al. SiMMap: A web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties. Nucleic Acids Res 2010;38:W424-30.
25. Islam I, Brown G, Bryant J, Hrvatin P, Kochanny MJ, Phillips GB, et al. Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: Optimization of BX-517. Bioorg Med Chem Lett 2007;17:3819-25.
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RAMA ADIGA. “MOLECULAR DOCKING OF HYRTIMOMINE A-K FROM MARINE SPONGE HYRTIOS SPP. AS ANTICANCER TARGET OF PHOSPHOINOSITIDE-DEPENDENT KINASE 1”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 7, May 2019, pp. 130-5, doi:10.22159/ajpcr.2019.v12i7.33673.
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