Speaker
Description
Despite the ongoing research into cancer therapeutics, more than 10% of the population are still diagnosed with chronic myeloid leukemia (CML) annually. BCR-ABL protein has been identified as one of the most crucial causative targets of this disease. Inhibitors are currently available against this enzyme; however, recent studies have shown that T334I, and D381N mutations have become an unmet challenge. In this study, we explored the synergistic therapeutic effect of BCR-ABL co-inhibition, investigated the underlying structural dynamics and inhibitory mechanisms of Nilotinib and ABL001 combination therapy to overcome T334I, and D382N mutations. A wide range of in silico approaches were utilized to define and compare BCR-ABL’s structural dynamics and binding energy characteristics when jointly inhibited by Nilotinib and ABL001 compared with the effect of each drug alone. Molecular dynamic simulations reveal that the joint blockade of BCR-ABL by Nilotinib and ABL-001 renders a synergistic effect on BCR-ABL by inducing a more stable and compact protein conformation. The binding energy analysis showed that the joint effect of the two drugs were much better when combined compared with the binding effects of each drug alone. Our results provide a rational basis for the combination therapy using both inhibitors for BCR-ABL pathway in CML treatment.
Presenter Biography
PhD student
