Significance of BCR-ABL P-loop point mutations (L248R/V) on binding to FDA approved drugs: molecular dynamics simulations and DFT studies

The BCR-ABL fusion protein with dysregulated tyrosine kinase activity is the cause of chronic myelogenous leukemia (CML). Mutations in the P-loop, gatekeeper, catalytic and activation loop, within its kinase domain leads to drug resistance while treating CML. The mutation driven drug resistance mechanisms at the atomic level in BCR-ABL needs to be unravelled. This work aims to study the structural, dynamical, and functional effects of the P-loop point mutations on BCR-ABL kinase. In this work, the five main FDA approved drugs Imatinib, Dasatinib, Nilotinib, Ponatinib, Bosutinib and one investigational drug Rebastinib were analysed using molecular dynamics (MD), post-MD analyses and quantum chemical (QM) approaches. The P-loop residue L248 and its point mutations (L248R/V) forming direct interactions with the drug were validated. The root-mean-square deviation analysis suggests that Imatinib, Dasatinib and Nilotinib are promising drugs for L248 and L248R/V point mutations, followed by Rebastinib, Ponatinib, and Bosutinib, despite minor variations. The R and C-spines of the wild and mutant systems differ significantly, indicating that the protein backbone is directly affected by mutation. For all the considered wild and mutated amino acid-drug complexes, the interaction energy for L248R complexes is high compared to L248 and L248V complexes. The frontier molecular orbitals, HOMO-LUMO gap, and electrostatic potential maps were analysed. The MD simulations and QM studies suggest that L248 residue and its point mutations (L248R/V) are responsible for high affinity binding of BCR-ABL kinase with the drugs considered for the study.