IN SILICO STUDY OF IODINATED 5,10,15,20-TETRAKIS(4-AMINOPHENYL) PORPHYRIN AS RADIOPHARMACEUTICALS CANDIDATE FOR CHRONIC MYELOID LEUKEMIA THERAPY AGAINST BCR-ABL1T315I

• Main Author: Kurniawan, Michael
• Format: Final Project
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/74253
• Institution: Institut Teknologi Bandung

5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) is a porphyrin-derived compound that has potential as a radiopharmaceutical ligand. TAPP labeled with the radionuclide Iodine-131 can be used as a therapeutic candidate for chronic myeloid leukemia (CML) cancer. CML is caused by the expression of BCR-ABL1, inducing abnormal proliferation of white blood cells. CML therapy can be performed by tyrosine kinase inhibitors (TKIs) against BCR-ABL1. However, emergence of BCR-ABL1 resistance to TKIs causes therapeutic failure due to the mutation of threonine to isoleucine at the residue number of 315 (T315I). In this research, interaction studies through docking simulations were conducted to predict the affinity of iodinated TAPP against wild type and T315I mutant BCR-ABL1. The 3D structures of wild type BCR-ABL1 with imatinib as reference compound (PDB code 2HYY) and T315I mutant BCR-ABL1 with ponatinib as reference compound (PDB code 3IK3) were downloaded from the RCSB Protein Data Bank website. Geometry optimization for candidate ligand was performed using GaussView 5.0.8 and Gaussian09 software. Docking simulation was performed using AutoDock 4.2.6 and MGLTools 1.5.6 software. The docking simulation results were analyzed with BIOVIA Discovery Studio Visualizer 2021 software. Docking results for BCR-ABL1 in complex with reference compound, TAPP, and TAPP-5 binding free energy (?G) values of ?15.75, ?3.67, and ?3.51 kcal/mol (wild type) and ?15.48, +2.60, and +7.94 kcal/mol for (T315I mutant) were obtained respectively. Conformation of TAPP and iodinated TAPP from the docking results did not form hydrogen bonds with Thr315 and Met318 as in the reference compound. The iodine on TAPP provides hydrophobic interaction on BCR-ABL1 and steric hindrance on Ile293 and Asp381 on T315I mutant. Analysis of docking simulation shows that TAPP has affinity to BCR-ABL1 wild type weaker than reference compound but has poor affinity to BCR-ABL1 T315I mutant caused by steric hindrance at Lys271. Iodine labeling of TAPP has no significant impact on the affinity to BCR-ABL1 wild type protein but reduce the affinity to BCR-ABL1 T315I mutant.