POTENCY OF IODINATED 5,10,15,20-TETRAKIS(4-AMINOPHENYL) PORPHYRIN AS RADIOPHARMACEUTICALS FOR CHRONIC MYELOID LEUKEMIA: IN SILICO STUDY

• Main Author: Kurniawan, Michael
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/85364
• Institution: Institut Teknologi Bandung

5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) is a porphyrin derivative with potential as a radiopharmaceutical ligand. TAPP labeled with the radionuclide Iodine-131 can be used as an anticancer agent targeting BCR-ABL1 and BRD4 oncoproteins. BCR-ABL1 is involved in the pathology of Chronic Myeloid Leukemia (CML). Therapy failure in CML patients can occur due to BCR-ABL1 resistance to tyrosine kinase inhibitors caused by mutations, such as the threonine to isoleucine mutation at residue 315 (T315I). BRD4 is a protein in the bromodomain family involved in epigenetic mechanisms through chromatin modifications, leading to uncontrolled cell growth. Interaction studies were conducted through docking and molecular dynamics simulation to predict the affinity and interactions of iodinated TAPP towards wild-type BCR-ABL1, T315I mutant, and BRD4. The 3D structures of wild-type BCR- ABL1 (PDB ID: 1IEP), T315I-mutated BCR-ABL1 (PDB ID: 3IK3), and BRD4 (PDB ID: 4UIZ) were obtained from RSCB Protein Data Bank. Docking was carried out using AutoDock 4.2.6 and MGLTools 1.5.6 software. Subsequently, molecular dynamics simulations were carried out for 200 ns for BCR-ABL1 and 300 ns for BRD4 using Amber22 software. From the molecular dynamics results, TAPP, TAPP-1, TAPP-4, and TAPP-5 formed interactions with several key residues in wild-type BCR-ABL1 such as Thr315 and Asp381 and formed new interactions with Glu316. while TAPP-1, and TAPP-4 formed hydrogen bond interactions with Glu316 and Asp381 in T315I-mutated BCR-ABL1. Tested ligands could not interact with Met318 residue in the gatekeeper residue area of BCR-ABL1. TAPP, TAPP-2, and TAPP-4 formed hydrogen bonds with key residue Asn140 in BRD4. MMPBSA calculations on each of protein’s native ligands and TAPP-4 against those protein provided binding free energy (?G) values of ?45.9 and ?50.76 kcal/mol for wild-type BCR-ABL1, ?46.34 and ?50.27 kcal/mol for T315I-mutated BCR-ABL1, and ?27.26 and ?35.49 kcal/mol for BRD4. Labeling TAPP with three iodines on the aminophenyl groups (TAPP-4) provides interaction with some of the key residues of BCR-ABL1 and BRD4 and provides better free binding energy value than the available TKI. TAPP-4 carrying radioisotope Iodine-131 can be researched further as a radiopharmaceutical ligand for CML therapy, utilizing TAPP affinity to BCR-ABL1 and BRD4, and the radioiodine that can emit beta-particle to induce CML cells death.