ANALISIS POTENSI SENYAWA GOLONGAN FLAVONOID DAN XANTHONE DARI BERBAGAI EKSTRAK TUMBUHAN INDONESIA SEBAGAI INHIBITOR MEK1 DAN ERK2 MENGGUNAKAN PENDEKATAN MOLECULAR DOCKING

• Main Author: Fitri Aniza, Nadila
• Format: Final Project
• Language: Indonesia
• Subjects: Ilmu hayati ; Biologi
• Online Access: https://digilib.itb.ac.id/gdl/view/61370
• Institution: Institut Teknologi Bandung

Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to surrounding tissues. This phenomenon is the result of accumulation of multiple DNA mutations in cancer cells. One of the most deregulated pathways in cancer is the classical MAPK pathway, which is hyperactive and is responsible for 40% of human cancers. MEK1 is a direct activator of the ERK1/2 protein, which plays an important role in the process activation of many transcription factors involved in the expression of regulatory proteins for cell proliferation and survival. Currently there are alrady commercial anticancer drugs, for-instance trametinib and ulixertinib, which can inhibit MEK1 and ERK2 specifically. However, both drugs is can cause unwanted side effects. Therefore, the search for MEK1 and ERK2 inhibitors that have lower side effects is still being carried out. Bioactive compounds extracted from plants, such as flavonoids and xanthones, have been tested on various cell lines and have good potential anticancer activity with low toxicity. In this study, flavonoid and xanthone compounds, namely alpha mangostin, artonin e, artonin o, bractatin, calotetrapterins b, cochinchinone c, cryptocaryone, garcinone d, infectocaryone, and morellic acid, were tested in silico through the molecular docking method with the aim to find out the potential and to predict mechanism of inhibition against MEK1 and ERK2 through the formed interactions. Molecular docking simulations were performed using Autodock Vina 1.1.2. The docking simulation results were visualized using Pymol and the inhibition mechanism was analyzed using Ligplot+ v.2.2. The results showed that artonin o and alpha mangostin had the potential to be MEK1 and ERK2 inhibitors, with binding affinity values of 10.7; 8.8 kcal/mol and -9.6; -9.5 kcal/mol. Cryptocaryone are also known to have potential as MEK1 inhibitors with a binding affinity value of -9.2 kcal/mol, while calotetrapteins b compounds have potential as ERK2 inhibitors with a binding affinity value of -9.9 kcal/mol. Hydrogen bond and hydrophobic interactions with important residues, including Lys97, Met143, HRD motif, DFG motif, Ser212, and the activation segments Leu215, Ile216, Met219, stabilize the interaction between artonin o, alpha mangostin, and cryptocaryone in MEK1. Furthermore, the stabilization of interaction between artonin o, alpha mangostin and calotetrapterins b on ERK2 occurs due to hydrogen and hydrophobic interactions at the Lys54 and Asp167 residues. In summary, artonin o and alpha mangostin may inhibit MEK1 and ERK2 simultaneously, cryptocaryone and calotetrapterins have potential to inhibit MEK1 and ERK2 respectively. The results of this study can provide an initial reference for the development of MEK1 and ERK2 inhibitors based on natural compounds of the flavonoid and xanthone groups.