THE SELECTION OF NATURAL COMPOUNDS FROM INDONESIAN MEDICINAL PLANTS AS CANDIDATES OF AKT AND KRAS G12D INHIBITORS USING MOLECULAR DOCKING STUDY APPROACH

• Main Author: Aisyah
• Format: Theses
• Language: Indonesia
• Subjects: Teknologi
• Online Access: https://digilib.itb.ac.id/gdl/view/61265
• Institution: Institut Teknologi Bandung

Resistance to anti-EGFR in colorectal cancer treatment may arise from the PTEN loss of function or KRAS G12D mutation. These events trigger the activation of EGFR major downstream signaling pathways which are PI3K-AKT or RAS-MAPK although the EGFR has been inhibited by anti-EGFR. Inhibition of these signaling pathways by AKT or KRAS G12D inhibitors offers a solution for anti-EGFR resistant patients. Currently, the KRAS G12D inhibitor candidates have not successfully entered clinical trials, while several AKT inhibitor candidates in clinical trials have not shown significant inhibitory effects. Therefore, the exploration of new compounds with optimal inhibitory effects toward AKT or KRAS G12D proteins is necessary. These new compounds can be derived from plants. Based on the explanation, this study was conducted to find natural compounds from Indonesian medicinal plants to be potentially developed as AKT or KRAS G12D inhibitors using molecular docking approach. The natural compounds from Indonesian medicinal plants were selected by in-silico utilizing oral drug parameters include molecular weight, solubility, GI absorption, and Lipinski`s drug-likeness. The refinement procedure was applied to the protein structure of AKT1, KRAS G12C, KRAS G12D, and KRAS wild type. The natural compounds that passed the in-silico selection were used as ligands and docked into ATP-binding pocket of AKT1 and the SII-P/SII-G allosteric site of KRAS G12C, KRAS G12D, and KRAS wild type. The determination of potential natural compounds was done by analyzing the AutoDock Vina scoring function along with the analysis of hydrogen and hydrophobic bonds in the interaction of ligand with the important residues within protein binding site. In this study, 1311 natural compounds from 320 Indonesian medicinal plant species were used in in-silico selection. 327 of 1311 natural compounds in selection met the oral drug parameters. The results of ligands docking in AKT1 protein showed the affinity binding score of morindone (-9.1 kcal/mol) and porphyrin (-9 kcal/mol) were better than control compounds AZD5363 (-7.9 kcal/mol) and GDC0068 (-8.1 kcal/mol). Morindone and porphyrin also interacted with more important residues than control compounds. The results of ligands docking in KRAS proteins exhibited phaseollin had best affinity binding score toward KRAS G12C (-8.7 kcal/mol) and KRAS G12D (-7.5 kcal/mol). The affinity binding score of phaseollin was better in KRAS mutants than KRAS wild type (-6.2 kcal/mol). These results implied phaseollin inhibitory effect might be only working in KRAS mutants. Phaseollin was able to make interaction with the mutation point D12 in KRAS G12D but not with other KRAS, it would allow phaseollin gaining good specificity in targeting KRAS G12D. According to the results of this study, it was found natural compounds from Indonesian medicinal plants namely morindone, porphyrin, and phaseollin were potential to be developed as AKT or KRAS G12D inhibitors.