STUDI IN SILICO MUTASI CYP124 UNTUK MENINGKATKAN POTENSI AKTIVITAS HIDROKSILASI TERHADAP FARNESIL DIFOSFAT

• Main Author: Khansa, Febilia
• Format: Final Project
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/69414
• Institution: Institut Teknologi Bandung

Malaria is one of endemic disease in tropic and subtropic countries with wide impact. Currently, Artemisinin-Based Combination Therapy (ACTs) is the first-line drug for malaria. Artemisinin is obtained from A. annua plant. Amorphadiene synthase (ADS) enzyme is the center of artemisinin biosynthesis that able to catalyze the conversion of farnesyl diphosphate (FDP) to amorpha-4,11- diene. Later to be known, the use of 12-OH FDP as substrate of ADS enzyme needs only one oxidation step to produce aldehyde dihydroartemisinin (DHAAI). In this study, docking simulations and molecular dynamics (MD) simulation of CYP124 enzyme which has ?-hydroxilation activity against methyl branched lipids were done to obtain a reference modification of CYP124 enzyme that able to optimally hydroxylate FDP. The 3D protein structure was downloaded from the RCSB Protein Data Bank page with codes 2WM4 and 2WM5. Docking simulations were performed using Autodock 4.2 and MGLTools 1.5.6 software using the Lamarckian Genetic Algorithm search method. The docking simulation results are then visualized and analyzed using the BIOVIA Discovery Studio Visualizer 2021 and LigPlot+ v.2.2.5 applications. Then, 3 ns molecular dynamics simulations were performed on GROMACS 2020.7 software, using CHARMM22 protein force field and TIP3P water model. Mutation process and 3D enzyme modelling were carried out by Swiss-PDB Viewer v.4.1 software. The docking and molecular simulations showed the enzyme with mutations at residues ILE 96 into THR and LEU 198 into PHE had the best interaction with FDP and possibly increased the hydroxylation activity of FDP. Based on these results, further in vitro research should be done to see the effectiveness of hydroxylation process between CYP124 protein and FDP compounds.