An in silico approach to analyse imatinib analogues as effective protein kinase inhibitors against BCR-ABL in chronic myeloid leukemia

摘要

Chronic myelogenous leukemia (CML), is a heterogeneous clonal myeloproliferative disorder, which occurs from the neoplastic transformation of the primitive hematopoietic stem cell. The presence of a balanced translocation t(9;22) (q34;q11), known as the Philadelphia (ph) chromosome which is the basis of the diagnosis and the hallmark of the treatment. The chromosomal translocation results in the reciprocal fusion of the BCR to the ABL gene to form the chimeric BCR-ABL gene. The current project has focused on computational analysis of protein kinase inhibitors that target the kinase domain of BCR-ABL which are structurally related to imatinib. The protein kinase inhibitors was assessed for the inhibition property against CML from the Protein Data Bank (PDB). The ligand with significant higher binding energy compared to Imitinib were validated for drug likeness on ADMET toxicity screening tool. Intriguingly all the fatty acids showed docking energy in the range of -3.0 to -9.5 Kcal/mol. Among the different ligands, Alvocidib exhibited best affinity for the target as evident by the strong interaction with the target proteins in Ligplot. The in silico ADME results further substantiated the efficacy of Alvocidib showed as a potential natural source which could inhibit the tyrosine kinase activity of the BCR-ABL.