In Silico Identification and Analysis of Drug Resistant Mutants of ABL Tyrosine Kinase Based on Detrimental Missense Mutations

R.      Rajasekaran; C.      George Priya Doss; G.      Arun Prasad; Rao      Sethumadhavan

Abstract

In this work, we computationally identified the most detrimental missense mutations of ABL tyrosine kinase in Chronic Myelogenous Leukemia (CML) and analyzed the drug resistance from these detrimental missense mutations. Out of 45 missense mutations, 20 variants were commonly found less stable, deleterious and damaging by I-Mutant2.0, SIFT and PolyPhen programs respectively. Subsequently, we performed modeling of these 20 variants to understand their change in conformations with respect to native ABL tyrosine kinase by computing their RMSD (Root Mean Square Deviation). Further, the native and 20 mutants were docked with the drug ‘imatinib’ to find out the drug resistance of these detrimental missense mutations. Among the 20 mutants, we found by docking studies that 12 mutants, namely M244V, Q252H, Y253H, K285N, T315I, F317L, F317I, S349L, M351T, E355G, S417Y and W430L had less binding affinity with imatinib than the native type. Finally, we analyzed that the loss of binding affinity of these 12 mutants were due to altered flexibility in their binding amino acids with imatinib as compared with native type by normal mode analysis. In our work, we found the novel data that majority of the drug binding amino acids in those 12 mutants had encountered the loss of flexibility which could be the theoretical basis for the cause of drug resistance.

Keywords: Missense mutation, ABL tyrosine kinase, Imatinib, Modeling, Docking, Flexibility, Chronic Myelogenous Leukemia, Adenosine triphosphate, Swissprot, Protein Data Bank, I-Mutant 2.0, SIFT, PolyPhen, DDG, Tolerance index, PSIC SD, RMSD, Force Field, Gromacs, Atomic Contact Energy, PatchDock, Normal mode analysis, B-factors, ElNemo, Ligand Contact Tool