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In this work, the four main drugs for the treatment of chronic myeloid leukemia were analyzed, being imatinib, dasatinib, nilotinib and ponatinib followed by four derivative molecules of nilotinib and ponatinib. For these derivative molecules, the fluorine atoms were replaced by hydrogen and chlorine atoms in order to shade light to the structural effects on this set of inhibitors. Electronic studies were performed at density functional theory level with the B3LYP functional and 6-311+G(d,p) basis set. The frontier molecular orbitals, gap HOMO-LUMO, and NBO were analyzed and compared to docking studies for mutant T315I tyrosine kinase protein structure code 3IK3, in the DFG-out conformation. Structural similarities were pointed out, such as the presence of groups common to all inhibitors and modifications raised up on new generations of imatinib-based inhibitors. One of them is the trifluoromethyl group present in nilotinib and later included in ponatinib, in addition to the 1-methylpiperazin-1-ium group that is present in imatinib and ponatinib. The frontier molecular orbitals of imatinib and ponatinib are contributing to the same amino acid residues, and the ineffectiveness of imatinib against the T315I mutation was discussed. Communicated by Ramaswamy H. Sarma.

Electronic and structural study of T315I mutated form in DFG-out conformation of BCR-ABL inhibitors