POTENTIAL CAFFEINE DERIVATE COMPOUND AS TYROSINE KINASE INHIBITOR ITK

• Main Author: Hakim Risqilah R, Annisa
• Format: Final Project
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/57299
• Institution: Institut Teknologi Bandung

Cancer is known to be the main that cause of death in the world. Based on the development process, cancer cells are normal cells that are transformed into dysplastic cells, where cell development occurs in a malignant or intensive. Cancer cells are able to carry out proliferation and metathesis unhindered and excessive. One of the proteins that play an important role in the formation of cancer cells is ITK (IL-2-Inducible T-cell Kinase). In ITK, overexpression of cytokine genes can cause signaling disorders and can lead into uncontrolled cell develpoment. So far, commercial inhibitors used in chemotherapy have many negative side effects. The side effect consist of disregulation or impaired secretion of cytokine genes, impaired immune response, infection, and antagonistic effect that appear when the inhibitors combined with other compound when it used. Therefore, the search for alternative compound that can inhibited ITK is still on research. Recent studied research related to ITK inhibitors have shown the inhibitory activity of staurosporin compounds (K252a) against ITK with an IC50 value of 0.35 µM. However, the IC50 value obtained is a bit large compared to other commercial inhibitor of ITK. In this research, caffeine-derived compounds to be tested to find out their inhibitory activity against ITK activity. Caffeine-derived ware choose based on the structure analysis of the compound in compared with the structure of commercial ITK inhibitors and base on their bioactivity as anticancer. In silico testing was carried out with molecular docking method on natural compounds derived from caffeine, erlotinib and pyrazine-2-carboxylic acid to ITK protein. Molecular docking method was conducted to determine the potential of caffeine derivative compounds based on affinity values , interaction analysis and the level of inhibition of these compounds. The docking score obtained from docking between 14 caffeine-derived compounds to ITK are -7.3 kcal/mol to -8.7 kcal/mol with the best binding affinity obtained at 1,3-dimethyl-7-[(3-nitrophenyl)methyl ]-2,3,6,7-tetrahydro-1H-purine-2,6- dione (41). From the interaction profile of the docking results, it is known that the mechanism of inhibition of compound 41 against ITK involves three catalytic residues, namely Glu406, Asp500 and Lys391 as well as Phe435 and Cys442 residues as gatekeeper. The interactions formed involved two hydrogen bonds (Glu406, Asp500) and eleven hydrophobic interactions (Val377, Lys391, Met410, Val419, Phe435, Cys442, Arg486, Asn487, Leu489, Ser499 dan Phe501). So, based on the docking score and interaction profile, caffeine derivative compound 41 can be excellent candidates for ITK inhibitors