MOLECULAR DOCKING AND MOLECULAR DYNAMIC STUDIES OF STILBENE DERIVATIVE COMPOUNDS AS SIRTUIN-3 (SIRT3) HISTONE DEACETYLASE INHIBITOR ON MELANOMA SKIN CANCER AND THEIR TOXICITIES PREDICTION

Fauzan Zein Muttaqin

doi:10.36465/jop.v2i2.489

MOLECULAR DOCKING AND MOLECULAR DYNAMIC STUDIES OF STILBENE DERIVATIVE COMPOUNDS AS SIRTUIN-3 (SIRT3) HISTONE DEACETYLASE INHIBITOR ON MELANOMA SKIN CANCER AND THEIR TOXICITIES PREDICTION

Fauzan Zein Muttaqin

Abstract

Reseptor SIRT3 (sirtuin-3) diketahui mampu menjaga level Spesies Oksigen Reaktif / Reactive Oxygen Species (ROS) pada jumlah yang sesuai dalam menjaga proliferasi sel dan sejumlah agresifitas fenotip yang mampu mencegah apoptosis dan menyebabkan karsinogenesis. Pengujian in vitro menunjukkan bahwa senyawa stilben 4׳-bromo-resveratrol memiliki potensi kuat dalam menghambat aktivitas SIRT3 pada sel melanoma manusia dengan mencegah proliferasi sel dan menginduksi apoptosis. Penelitian ini bertujuan untuk mengkaji interaksi dan afinitas senyawa derivat stilben terhadap reseptor hSIRT3 melalui simulasi docking. Interaksi yang terjadi dipelajari melalui simulasi dinamika molekul yang menggambarkan kestabilan interaksi antara protein ‒ ligan. Prediksi toksisitas dilakukan guna mengkaji keamanan dan toksisitasnya terhadap tubuh manusia. Validasi docking dilakukan dengan me-redocking ligan alami (4׳-bromo-resveratrol) dari reseptor target hSIRT3 (kode PDB 4C7B) dengan hasil nilai RMSD 1,88 Å. Simulasi docking terhadap 20 senyawa uji diperoleh 10 senyawa uji dengan afinitas terbaik yang akan dilanjutkan ke tahapan simulasi dinamika molekul. Persiapan file topologi kesepuluh senyawa uji dan protein target dilakukan sebelum simulasi dinamika molekul. Hasil simulasi dinamika molekul selama 10 ns menunjukkan bahwa senyawa Tetrahidroksistilben-2, Arahipin-10 dan Gnetin-L memiliki kestabilan interaksi yang baik terhadap hSIRT3 yang ditunjukkan oleh kecenderungan grafik RMSD yang konstan selama simulasi. Hasil prediksi toksisitas 20 senyawa uji diperoleh bahwa sebesar 83% senyawa uji tidak menimbulkan toksisitas.Berdasarkan penelitian tersebut, diketahui bahwa senyawa Tetrahidroksistilben-2 paling berpotensi menjadi kandidat senyawa inhibitor hSIRT3 dengan afinitas tertinggi dan resiko toksisitas yang minimal.

Keywords

Hylocereus polyrhizus, Achantina Fulica., gel, cycling test

Full Text:

PDF

References

Hamilton, E.C., Austin, M.T. (2016), Childhood and Adolescent Melanoma—Where Do We Stand Today?, Internal Medicine Review.

American Cancer Society (ACS). (2017), Overview : Melanoma Skin Cancer – About Melanoma Skin Cancer.

Hendaria, M.P., Asmarajaya, A., Maliawan, S. (2013), Kanker Kulit, medika udayana. 2, 2, 1 – 17.

Madonna, G., Ullman, C.D., Gentilcore, G., Palmieri, G., Ascierto, P.A. (2012), NF-κB as potential target in the treatment of melanoma, Journal of Translational Medicine, 10, 53.

Ansari, A., Rahman, S.M., Saha, K.S., Saikot, K.F., Deep, A., Kim, H.K. (2016), Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease, Aging Cell, 1 – 13.

Chen, Y., Fu, L.L., Wen, X., Wang, X.Y., Liu, J., Cheng, Y., Huang, J. (2014), Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer, Cell Death and Disease, 5, e1047.

George, J., Nihal, M., Singh, K.C., Nihal, A. (2015), Small molecule SIRT3 inhibitor 4′-bromo-resveratrol inhibits proliferation, promotes apoptosis and causes metabolic reprograming of human melanoma cells, AACR : Molecular and Cellular Biology.

George, J., Nihal, M., Singh, K.C., Zhong, W., Liu, X., Nihal, A. (2016), Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma, Journal of Investigative Dermatology.

Nguyen, G.T.T., Gertz, M., Steegborn, C. (2013), Crystal Structures of Sirt3 Complexes with 40-Bromo-Resveratrol Reveal Binding Sites and Inhibition Mechanism, Chemistry & Biology. 20, 1375 – 1385.

Pangastuti, A., Amin, M., Indriwati, S.E. (2016), Mengungkap potensi senyawa alami melalui teknik Reverse Docking, Prosiding Seminar Nasional II, Malang, Universitas Muhammadiyah Malang, 668 – 674.

Adelina, R. (2014), Uji Molecular Docking Annomuricin E dan Muricapentocin pada Aktivitas Antiproliferasi, Jurnal Ilmu Kefarmasian Indonesia, 12, 1, 32 – 36, ISSN 1693 – 1831.

Kartasasmita, R.E., Herowati, R., Harmastuti, N., Gusdinar, T. (2009), Docking Turunan Kuersetin Berdasarkan Studi Interaksi Flavonoid Terhadap Enzim Siklooksigenase-2, Indonesian Journal of Chemistry, 9, 2, 297 – 302.

Bissantz, C., Kuhn, B., Stahl, M. (2010), A Medicinal Chemist’s Guide to Molecular Interactions, Journal of Medicinal Chemistry, 53, 5061 – 5084.

Torshin, I.Y., Weber, I.T., Harrison, R.W. (2002), Geometric criteria of hydrogen bonds in protein and identification of ‘bifurcated’ hydrogen bonds, Protein Engineering, 15, 5, 359 – 363.

Desheng, L., Jian, G., Yuanhua, C., Wei, C., Huai, Z., Mingjuan, J. (2011), Molecular dynamics simulations and MM/GBSA methods to investigate binding mechanisms of aminomethylpyrimidine inhibitors with DPP-IV, Bioorganic and Medicinal Chemistry Letter, 21, 6630 – 6635.

Setiajid, M.A. (2012), Analisis Dinamika Molekuler Hasil Penambatan Molekul Kompleks Sikolooksigenase-2 Dengan Beberapa Senyawa 3-fenil-2-stiril-4(3H)-kuinazolinon Tersubstitusi Sulfonamida Atau Sulfasetamida, Skripsi Program Sarjana, Universitas Indonesia, 26 – 38.

Farkhani, A. (2012), Analisis Dinamika Molekuler Hasil Penambatan Kompleks α-Glukosidase dengan Sulokrin, Skripsi Program Sarjana, Universitas Indonesia, 52 – 53.

CambridgeSoft Corporation (Cambridge Scientific Computing, Inc.). (2009), ChemOfficeTM User Manual, Cambridge, USA.

Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V., Cioslowski, J., Fox, D.J. (2009), Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT.

Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K. Goodsell, D.S., Olson, A.J. (2009), AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility, Journal of Computational Chemistry, Vol.30, No.16, 2785 – 2791.

Abraham, M.J., Spoel, van der D., Lindahl, E., Hess, B., and the GROMACS development team. (2015), GROMACS User Manual version 5.1.1. (www.gromacs.org).

Simulation Plus Inc. (2016), ADMET PredictorTM User Manual, California, USA.

Cole, J.C., Murray, C.W., Nissink, J.W.M., Taylor, R.D., Taylor, R. (2005), Comparing Protein – Ligand Docking Programs Is Difficult, PROTEINS : Structure, Function, and Bioinformatics, 60, 3, 325 – 332.

DOI: http://dx.doi.org/10.36465/jop.v2i2.489

Refbacks

There are currently no refbacks.

p-ISSN: 2620-8563; e-ISSN: 2621-1521

Index:

Username
Password
Remember me