A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR–ABL1 Resistance

  • Ahmed A. El Rashedy
  • Patrick Appiah-Kubi
  • Mahmoud E. S. SolimanEmail author


The constitutive BCR–ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR–ABL1 confer drug resistance. Recent experimental studies show a synergistic effect in suppressing this resistance when Nilotinib and Asciminib are co-administered to target both the catalytic and allosteric binding site of BCR–ABL1 oncoprotein, respectively. However, the structural mechanism by which this synergistic effect occurs has not been clearly elucidated. To obtain insight into the observed synergistic effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as the structural dynamics that characterize this effect. Structural dynamic analyses indicate that the synergistic binding effect results in a more compact and stable protein conformation. In addition, binding free energy calculation suggests a dominant energy effect of nilotinib during co-administration. van der Waals energy interactions were observed to be the main energy component driving this synergistic effect. Furthermore, per-residue energy decomposition analysis identified Glu481, Ser453, Ala452, Tyr454, Phe401, Asp400, Met337, Phe336, Ile334, And Val275 as key residues that contribute largely to the synergistic effect. The findings highlighted in this study provide a molecular understanding of the dynamics and mechanisms that mediate the synergistic inhibition in BCR–ABL1 protein in chronic myeloid leukemia treatment.


BCR–ABL1 Mutation CML Asciminib (ABL001) Nilotinib Allosteric inhibitor Molecular dynamics 



The authors acknowledge the College of Health Science, the University of KwaZulu-Natal for financial support and Centre of High-Performance Computing (CHPC) Cape Town, RSA, for computational resources (

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Molecular Bio-computation and Drug Design Lab, School of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa
  2. 2.College of Pharmacy and Pharmaceutical SciencesFlorida Agricultural and Mechanical University, FAMUTallahasseeUSA

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