Docking Molekuler Dan Studi Farmakofor Senyawa Trisindolina 1 sebagai Kandidat Inhibitor Jalur MAPK Kanker Hati

Lianingsih, Fitri (2021) Docking Molekuler Dan Studi Farmakofor Senyawa Trisindolina 1 sebagai Kandidat Inhibitor Jalur MAPK Kanker Hati. Masters thesis, Institut Teknologi Sepuluh Nopember Surabaya.

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Abstract

Kanker hati merupakan jenis kanker dengan pertumbuhan mencapai 72.5% di Asia pada tahun 2018. Salah satu jalur yang dapat mempengaruhi kanker hati adalah hiperaktivasi jalur MAPK (mitogen activated protein kinase). Jalur MAPK diaktivasi pada 50 - 100% hepatocellular carcinoma (HCC) dan berhubungan dengan prognosis yang buruk. MAPK merupakan salah satu jalur stimulus dalam modifikasi eksternal, respon interseluler dan beberapa faktor post transkripsi yang dapat menstabilkan inflamasi, diferensiasi sel dan apoptosis. MAPK berperan penting dalam fungsi fisiologis seperti menjaga homeostasis. Stress ekstraseluler dapat menginduksi aktivasi MAPK pada kondisi patologis. Aktivasi MAPK berperan penting dalam mengatur inflamasi terkait perkembangan kanker sehingga MAPK dianggap sebagai target terapi yang menjanjikan. Spons laut Hyrtios altum dengan bakteri simbion menghasilkan metabolit sekunder golongan alkaloid yaitu Trisindolina. Riset sebelumnya menunjukkan bahwa senyawa Trisindolina 1 (5’-nitro-[3,3’:3’,3”-terindolin]-2’-one) memiliki efek aktivitas sitotoksisitas yang tinggi terhadap sel kanker hati HepG2. Penelitian ini bertujuan untuk mengetahui aktivitas Trisindolina 1 secara in silico dengan target jalur MAPK pada kanker HepG2 dan identifikasi farmakofor secara fisikokimia. Metode yang dilakukan adalah docking molekuler menggunakan AutoDock terhadap protein ERK1, JNK2 dan p38 pada jalur MAPK dengan kontrol positif obat Doxorubicin. Analisis farmakofor dilakukan menggunakan SwissADME untuk mengetahui sifat kemiripan obat (druglikeness) dan sifat fisikokimia. Hasil docking menunjukkan bahwa Trisindolina 1 berpotensi sebagai inhibitor protein ERK2, JNK1, dan p38 jalur MAPK pada kanker hati melalui skor docking. Berdasarkan hasil analisis The Rule of Five by Lipinski, senyawa Trisindolina 1 telah memenuhi parameter sifat mirip obat druglikeness karena memenuhi nilai optimum yang disarankan. Senyawa Trisindolina 1 memiliki kemiripan dengan golongan isatin dan turunannya dengan mekanisme menghambat jalur MAPK kanker hati melalui autofagi dan apoptosis. ========================================================================================================= Liver cancer is a type of cancer with a growth of 72.5% in Asia in 2018. One of the pathways that can affect liver cancer is hyperactivation of the MAPK (mitogen activated protein kinase) pathway. The MAPK pathway is activated in 50–100% hepatocellular carcinoma (HCC) and is associated with a poor prognosis. MAPK is one of the stimulus pathways in external modification, intercellular responses and several post-transcription factors that can stabilize inflammation, cell differentiation and apoptosis. MAPK plays an important role in physiological functions such as maintaining homeostasis. Extracellular stress can induce MAPK activation in pathological conditions. Activation of MAPK plays an important role in regulating inflammation related to cancer development so that MAPK is considered a promising therapeutic target. Sea sponge Hyrtios altum with symbiont bacteria produces a secondary metabolite of the alkaloid group, Trisindoline. Previous research has shown that the compound Trisindoline 1 (5'-nitro- [3,3 ': 3', 3 "-terindoline] -2'-one) has a high cytotoxic activity effect against HepG2 liver cancer cells. This study aims to determine the activity of Trisindoline 1 in silico by targeting the MAPK pathway in HepG2 cancer and physicochemical identification of pharmacophores. The method used was molecular docking using AutoDock against the ERK1, JNK2 and p38 proteins on the MAPK pathway with positive control of the drug Doxorubicin. Pharmacophores analysis was carried out using SwissADME to determine the druglikeness and physicochemical properties. The docking results showed that Trisindoline 1 has the potential as an inhibitor of the MAPK protein ERK2, JNK1, and p38 pathways in liver cancer. Based on the results of the analysis of the rule of five by Lipinski, the Trisindoline 1 compound has met the drug-like properties parameter druglikeness because it meets the recommended optimum value. Trisindoline 1 has similarities with the isatin group and its derivatives by inhibiting the MAPK pathway for liver cancer through autophagy and apoptosis.

Item Type: Thesis (Masters)
Uncontrolled Keywords: apoptosis, in silico, jalur MAPK, kanker hati, Trisindolina 1, apoptosis, in silico, liver cancer, MAPK pathway, Trisindoline 1
Subjects: Q Science > QH Biology
Divisions: Faculty of Science and Data Analytics (SCIENTICS) > Biology > 46101-(S2) Master Thesis
Depositing User: Fitri Lianingsih
Date Deposited: 05 Mar 2021 23:02
Last Modified: 05 Mar 2021 23:02
URI: https://repository.its.ac.id/id/eprint/83593

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