DESIGN AND IN SILICO STUDY OF DIAZOLYLPORHYRIN DERIVATIES AS A CANDIDATE OF RADIOPHARMACEUTICAL LIGAN KIT FOR MELANOMA CANCER

• Main Author: Kurniawan, Fransiska
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/78845
• Institution: Institut Teknologi Bandung

Melanomas are the most aggressive form of a skin cancer, which arises from melanocytes, especially pigmented cells which predominantly found in skin. Metastatic melanoma cancer is extremely difficult to be treated with current therapy method such as surgery. On the contrary, there is a good opportunity to develop a novel radiopharmaceutical using Rhenium (Re) for therapeutic purpose and common radiopharmaceutical using Technetium (Tc) for diagnostic purpose. Due to its properties, this novel radiopharmaceutical will work on cancer area selectively and hence cause less adverse effects. Water soluble porphyrin such as 5, 10, [3,4—bis— (carboxymethylenenoxy) phenyl] porphyrin (T3 4BCPP) has been reported to be experimentally applicable and effective as radioimaging for melanoma cancer. Therefore the purpose of the present research was to develop and obtain new diazolylporphyrin derivatives showing better selectivity and higher affinity than those of T3,4BCPP by means of in silico sudy. Eight types of Re- and Tc- labeled imidazolylporphyrin and eight types of Re- and Tc- labeled pirazolylporphyrin were optimized using Gaussian 09 package in order to obtain partial charge of each atom and docked into Fibroblast Growth Factor Receptor 1 (FGFRI, PDB ID: 5AM6) using AutoDock 4.2 software. To mimic biological condition of cancer cells, the receptor was simulated by molecular dynamic simulation for 30 ns using NAMD 2.10 at 37 oc. The obtained conformation was then applied in molecular docking simulation. Dovitinib (natural ligand of FGFRI), ReT34BCPP and Tc-T3 4BCPP were used as references. Molecular dynamic simulation resulted in the RMSD for FGFRI of 3.8 Å, confirming high variance in conformations of the FGFRI at —273 oc and 37 oc which in turn can affect molecular docking simulation. Docking simulation results revealed that Tc-T3 4BCPP has free binding energy of +1,31 kcal/mol and that of Re-T3,4BCPP is —(),01 kcal/mol. From all studied imidazolylporphyrin derivatives, Tc-cD3,4BCPMlP (Tc-5, enoxy)phenyl]-15,20-di-(l,2-dimethylimidazolium-4-yl)porphyrin) and Re-cD3,4BCPIP (Re-5,10-di-[3,4-bis-(carboxymethylenoxy)phenyl]-15,20-di-(methylimidazole-4-yl) porphyrin) gave the best docking result. Tc-cD3,4BCPMIP has free binding energy values of —4.06 kcal/mol with 10 hydrogen bonds whereas those of Re-cD3,4BCPIP was —4.35 kcal/mol with 7 hydrogen bonds. In the case of pi;azotylporphyrin derivatives, Tc- 4BCPPzP (Tc-5, pyrazole-4-yl)-porphyrin) and methylenoxy)phenyl]-15,20-di-(methyl-pyrazole-4-yl)-porphyrin) gave the best docking result. Tc-D3,4BCPPzP has free binding energy values of —6.45 kcal/mol with 4 hydrogen bonds whereas those of Re-cm 4BCPPzP was —4.07 kcai/mol with 7 hydrogen bonds. Considering overall results, it was concluded that cD3,4BCPIP and D3,4BCPPzP are the potential candidate ligand for melanoma cancer's radiöpharmaceutical kit with better selectivity than T3,4BCPP.