Evaluation of the inhibitory effect of Curcumin on Bcr-Abl Tyrosine Kinase Enzyme in Chronic Myeloid Leukemia by bioinformatics simulation method

Evaluation of the inhibitory effect of Curcumin on Bcr-Abl Tyrosine Kinase Enzyme in Chronic Myeloid Leukemia by bioinformatics simulation method
Zeinab Norouzi Tabrizi Nejad,^1,* Razieh Norouzi Tabrizi Nejad,²
1. Shahid Chamran University of Ahvaz
2. Ahvaz Jundishapur University of Medical Science
Introduction: Chronic Myeloid Leukemia (CML) is a type of Leukemia that affects the cells that make up bone marrow tissue. This type of chronic leukemia is caused by a small, abnormal chromosome in the blood and bone marrow called the Philadelphia chromosome, or Ph1. The Philadelphia chromosome is caused by the reciprocal translocation of the long arm of chromosome 22 with the long arm of chromosome 9. This reciprocal translocation causes the transfer of ABL (Abelson) cellular oncogenes from chromosome 9 to chromosome 22 in an area called fracture aggregation, or BCR,which produces a chimeric transcript derived from the c_ABL (70%) and BCR genes. The expression of this chimer gene is a fusion protein with BCR protein at the amine terminus and ABL protein at the carboxy terminus, which is associated with transforming activity. The BCR-ABL protein produced stimulates the production of large amounts of the protein Tyrosin Kinase, which increases cell proliferation and inhibits apoptosis and does not depend on cellular signaling pathways and it causes uncontrolled proliferation of abnormal cells and it causes a deficiency of normal blood cells. Curcumin in turmeric is an effective substance that destroys brain plaques. Curcumin triggers programmed cell death pathways or apoptosis if it can enter cancer cells and it does this by activating caspases 3, 7 and 9. The aim of this study was to compare the effect of Curcumin on the enzyme Tyrosine Kinase Bcr-Abl and the drugs used to inhibit this enzyme by bioinformatics simulation method.
Methods: The structure of Tyrosin Kinase Bcr-ABL(with Accession = 5OC7 ) enzyme was received from NCBI website (www.ncbi.nlm.nih.gov/protein) in .PDB format and energy minimization experiment were performed on GROMACS 4.6.5 software. This structure then refined for blind docking experiments in HEX 8.0.0. Structures of Drugs of Bosutinib, Dasatinib , Erlotinib , Imatinib , Nilotinib, Omacetaxine, Ponatinib and Curcumin were obtained from pubchem website (www.pubchem.ncbi.nlm.nih.gov) in .sdf format and converted .pdb format by OpenBable2.3.2 software and optimized in HyperChem7 software. The Malecular docking experiments were done using drugs to study their interactions and to survey their bind sites. Docking results were analyzed by ArgusLab, Raswin, WebLab Viewer, Excell2016 and LigPlus software.
Results: The results of this study showed that Curcumin, Erlotinib, Nilotinib and Imatinib bind to both enzyme chains and show greater inhibitory ability; and Ponatinib and Bosutinib are more closely linked to the C chain, while Omacetaxine and Dasatinib are more closely linked to the A chain. The maximum hydrophobicity coefficient of the binding site is related to Ponatinib which tends to bind to hydrophobic amino acids and the minimum hydrophobicity coefficient belongs to Dasatinib which tends to bind to hydrophilic amino acids in the active site. The results of this study showed that Nilotinib, Ponatinib and Imatinib have more negative binding energy.
Conclusion: Chronic Myeloid Leukemia is caused by a reciprocal translocation on chromosomes 9 and 22 and the formation of the Philadelphia chimeric chromosome and it follows the proliferation and incomplete evolution of white blood cells and is one of the most common cancers in children. This disease produces very large amounts of blood cells that are different from normal blood cells and stop the production of normal white blood cells, and reducing a person's ability to fight disease. These mutated cells also reduce the production of other blood cells, such as Red Blood Cells and Platelets, and are found in immunosuppression, anemia, and blood clotting disorders. In this study, it was observed that molecular weight and binding energy have a negative correlation with Sig = 0.020 and P-Value = -0.789 and by increasing the values of molecular weight , the binding energy is further reduced. Curcumin has a greater inhibitory effect than Erlotinib, Imatinib and Nilotinib due to its lower molecular weight.
Keywords: Curcumin, Tyrosin Kinase Bcr-ABL, Docking, Chronic Myeloid Leukemia, Philadelphia Chromosome