Molecular interactions of c-ABL mutants in complex with imatinib/nilotinib: a computational study using linear interaction energy (LIE) calculations.

In spite of the effectiveness of Imatinib for chronic myeloid leukemia (CML) treatment, resistance has repeatedly been reported and is associated with point mutations in the BCR-ABL chimeric gene. To overcome this resistance, several inhibitors of BCR-ABL tyrosine kinase activity were developed. In this context, computational simulations have become a powerful tool for understanding drug-protein interactions. Herein, we report a comparative molecular dynamics analysis of the interaction between two tyrosine kinase inhibitors (imatinib or nilotinib) against wild type c-ABL protein and 12 mutants, using the semi-empirical linear interaction energy (LIE) method, to assess the feasibility of this approach for studying resistance against the inhibitory activity of these drugs. In addition, to understand the structural changes that are associated with resistance, we describe the behavior of water molecules that interact simultaneously with specific residues (Glu286, Lys271 and Asp381) of c-ABL (wild type or mutant) and their relationship with drug resistance. Experimental IC50 values for the interaction between imatinib, wild type c-ABL, and 12 mutants were used to obtain the proper LIE coefficients (α, β and γ) to estimate the free energy of the binding of imatinib with wild-type and mutant proteins, and values were extrapolated for the analysis of the nilotinib/c-ABL interaction. Our results indicate that LIE was suitable to predict the superior inhibitory activity of nilotinib and the resistance to inhibition that was observed in c-ABL mutants. Additionally, for c-ABL mutants, the observed number of water molecules being turned over while interacting with amino acids Glu286, Lys271 and Asp381 was associated with resistance to imatinib, resulting in a less effective inhibition of the kinase activity.