MOLECULAR STUDY THE COMBINATION OF JBJ-04-125-02 AND OSIMERTINIB AS INHIBITORS OF DOUBLE MUTANT (T790M/V948R) AND TRIPLE MUTANT (T790M/C797S/V948R) EGFR MUTANTS AT ALLOSTERIC SITES AND ATP SITES

• Main Author: Rachmawati, Fithriana
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/76566
• Institution: Institut Teknologi Bandung

The most common type of lung cancer is the Non-Small Cell Lung Cancer (NSCLC) type, accounting for 80-85% of the total lung cancer sufferers in the world. Epidermal Growth Factor Receptor - Tyrosine Kinase Inhibitor (EGFR-TKI) is recommended as first-line treatment of advanced EGFR-mutant NSCLC. The problem with Tyrosine Kinase Inhibitor (TKI) class of drugs is drug resistance that continues to occur. This is due to mutations in the Epidermal Growth Factor Receptor (EGFR) that continue. Osimertinib is a third generation TKI that shows strong activity in inhibiting active and resistant EGFR mutations. Osimertinib as a second line in T790M patients can cause the emergence of an EGFR triple mutant with the most common mutation C797S in exon 20. Thus, the purpose of this study was conducted to determine the drug combination JBJ-04-125-02 and osimertinib at allosteric sites and ATP sites has the same activity. better than the single compound molecularly. The structures of JBJ-04-125-02 and osimertinib were optimized using Gaussian09 software. Then the 7JXW and 5ZWJ receptors were repaired using the homology modeling method using the UCSF Chimera and Modeller webservice applications. One structure was selected based on the zDOPE and RMSD values. Then the selected model is minimized using AMBER software. Validation was carried out using the MolProbity webserver before and after minimization. The best models 7JXW and 5ZWJ were then overlapped using the UCSF Chimera application to determine the ATP sites on 5ZWJ. Then the validated 7JXW and 5ZWJ structures were docked simulated using AutodockTools software on single compounds and combinations (JBJ-04-125-02 and osimertinib). Molecular dynamics simulations were carried out for 200 ns at 310°K. The homology modeling method produces one model out of five validated 5ZWJ and 7JXW structural models. Molecular binding to the 5ZWJ receptor shows a more negative free binding energy value, which is –13.94 kcal/mol, compared to the single compounds JBJ-04-125-02 and osimertinib which are –12.96 kcal/mol and respectively –6,73 kcal/mol. The same results were shown for the 7JXW receptor, where the value of the combined compound had a more negative free binding energy value for the combined compound, which was –14.88 kcal/mol compared to the single compound JBJ-04-125-02 and osimertinib respectively of –13,90 kcal/mol and –8,86 kcal/mol. The results of the dynamics simulation for 200 ns show a different value from the results of molecular docking, where the 5ZWJ 6 receptor for the single compound JBJ-04-125-02 has a more negative for average free binding energy value, which is –52.58 kcal/mol compared to the free binding energy value of the combination compound, which is –52.58 kcal/mol. The same thing happened to the 7JXW receptor, where the free binding energy value of the single compound JBJ-04-125-02 has a more negative free binding energy, which is –52.61 kcal/mol compared to the binding free energy value of the combination compound, which is –40.93 kcal/mol. Different things happen to osimertinib compounds. Where for both receptors, the combination of osimertinib compound produces an average free binding energy value that is more negative, which is - 31.17 kcal/mol at the 5ZWJ receptor and -30.06 kcal/mol at the 7JJXW receptor compared to the single compound, at the 5ZWJ receptor. of –30.48 kcal/mol and at the 7JXW receptor of –29.69 kcal/mol. It can be concluded that only the combination compound of osimertinib has a better affinity than the single compound for both 5ZWJ and 7JXW receptors.