POTENSI SENYAWA BULLATALISIN SEBAGAI INHIBITOR PROTEIN LEUKOTRIEN A4 HIDROLASE PADA KANKER KOLON SECARA IN SILICO

Harry Noviardi, Fachrurrazie Fachrurrazie

Abstract


ABSTRAK

Kanker kolon merupakan jenis kanker yang dapat menyebabkan kematian. Salah satu penyebabnya adalah pertumbuhan Leukotrien A4 hidrolase yang tidak terkontrol. Leukotrien A4 hidrolase dapat dijadikan target terapi dalam menekan pertumbuhan sel kanker. Bullatalisin merupakan senyawa turunan asetogenin yang memiliki potensi inhibitor terhadap Leukotrien A4 hidrolase. Penelitian ini bertujuan menentukan potensi Bullatalisin sebagai inhibitor secara in silico berdasarkan energi bebas Gibbs (?G), tetapan inhibisi, interaksi ikatan hidrogen serta Root Mean Deviation Square (RMSD). Penelitian dilakukan secara komputasi menggunakan metode molecular docking.Berdasarkan pada hasil analisis visualisasi interaksi docking, menunjukkan adanyainteraksi ikatan antara Bullatalisin dan residu asam amino dari kantung aktif Leukotrien A4 hidrolase. Selain itu nilai energi bebas Gibbs, tetapan inhibisi dan RMSD dari Bullatalisin tidak berbeda secara signifikan dibandingkan dengan ligan standar. Oleh karena itu, Bullatalisin diprediksi berpotensi sebagai inhibitor Leukotrien A4 hidrolase.

Kata kunci: bullatalisin, docking, in silico, kanker kolon, leukotrien A4 hidrolase


References


Arguello, M., Paz, S., Hernandez, E., et al. 2006. Leukotriene A4 hydrolase expression in PEL cells is regulated at the transcriptional level and leads to increased leukotriene B4 production. J Immunol. 176:7051-7061.

Boyle, N.M.O., Banck, M., James, C.A., et al. 2011. Open Babel: An open chemical toolbox. J. Cheminf. 3:33.Chen, X., Li, N., Wang, S., et al. 2003. Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. J Natl Cancer Inst. 95:1053-1061.Chen, X, Wang, S, Wu, N, Yang, C.S. 2004. Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Current cancer Drug Target. 4:267-283.

Chiu, H.F., Chih, T.T., Hsian, Y.M., Tseng, C.H., Wu, M.J., Wu, Y.C. 2003. Bullatacin, a potent antitumor Annonaceous acetogenin, induces apoptosis through a reduction of intracellular cAMP and cGMP levels in human hepatoma 2.2.15 cells.Biochem Pharmacol. 65(3):319-327.

Chul, H.J., Ann, M.B., Angelo, P., et al. 2009. [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res. 69: 5584-5591.DeLano, W.L. 2002. The PyMOL molecular graphics system. http://www.pymol.org.

Gilson, M.K., Zhou, H. X. 2007. Calculation of protein-ligand binding affinities. Annual Review of Biophysics and Biomolecular Structure. 36:21-42.

Haeggstrm, J.Z., Funk, CD. 2011. Lipoxygenase and leukotriene pathways: Biochemistry, biology, and roles in disease. Chem Rev. 111(10):5866-5898.

Hevener, K., Zhao, W., Ball, D., Babaoglu, K., Qi, J.J., White, S., Lee, R. 2009. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J of Chemical Information and Modeling. 46(2):444-460.

Idrees, S., Ashfaq, U.A. 2014. Discovery and design of cyclic peptides as dengue virus inhibitors through structure-based molecular docking.Asian Pacific Journal of Tropical Medicine. 7(7):513-516.

Liang, Y.J, Zhang, X, Dai, C.L., et al. 2009. Bullatacin Triggered ABCB1-Overexpressing Cell Apoptosis via the Mitochondrial-Dependent Pathway. Journal of Biomedicine and Biotechnology. 2009, Article ID 867123:1-9.

Marjolein, M.G.M.T, Nordlund, P., Haeggstrm,J.Z. 2001.Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation. Nature Structural Biology. 8:131-135.Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K., Olson, A.J. 1998. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 19(14):1639-1662.

Niegowski, D., Thunnissen, M., Tholander, F., Rinaldo-Matthis, A., Muroya, A., Haeggstrom, J.Z. 2102. Structure of human Leukotriene A4 hydrolase in complex with inhibitor sc57461A. http://www.rcsb.org/pdb/explore/explore.do?structureId=3U9W.

Okun, J.G., Lummen, P., Brandt, U. 1999. Three classes of inhibitors share a common binding domain in mitochondrial complex I (NADH:Ubiquinone oxidoreductase. The Journal of Biological Chemistry. 274(5):2625-2630.

Orning, L., Gierse, J.K, Fitzpatrick, F.A. 1994. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J Biol Chem 269(15):11269-11273.

Purnomo, H. 2013. Kimia komputasi: molecular docking plants penambatan molekul plants [protein-ligand-ant-system](ilmu semut). Pustaka Pelajar. Yogyakarta. 62-63.

Rester, U. 2008. From virtuality to reality - virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective. Current Opinion in Drug Discovery & Development.11: 559-568.

Santoyo, A.H., Barajas, A.Y.T., Altuzar, V., et al. 2013. Protein-Protein and Protein-Ligand Docking. In Tech. 64-81.

Seeliger, D., de Groot, B.L. 2010. Ligand docking and binding site analysis with PyMOL and AutoDock/Vina. J Comput Aided Mol Des. 24:417-422.

Sousa, S.F, Fernandes, P.A., Ramos, M.J. 2006. Protein-ligand docking: current status and future challenges. Proteins. 65(1):15-26.

Stsiapanavaa, A., Olssona, U., Wana, M., et al. 2014. Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. PNAS. 111(11):4227-4232.

Tambunan, U.S.F., Alamudi, S. 2010. Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach. Bioinformation. 5(6):250-254.

Tholander, F., et al. 2008. Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: Implications for M1 aminopeptidases and inhibitor design. Chem Biol. 15(9):920-929.

Thunnissen, M.M., Nordlund, P., Haeggstrom, J.Z. 2001. Crystal structure of human leukotriene A4 hydrolase, a bifunc- tional enzyme in inflammation. Nat Struct Biol. 8:131-135.

Trott, O., Olson, A. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J CompChem. 31:455-461.



Full Text: PDF

DOI: 10.33751/jf.v5i2.410

Refbacks

  • There are currently no refbacks.


Copyright (c) 2017 FITOFARMAKA

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.