Targeting kinase resistance in CML: Efficacy of phytoconstituents through molecular docking and dynamics simulations

Chronic myeloid leukemia (CML) is caused by the reciprocal translocation t(9;22)(q34;q11) which generates the BCR-ABL1 fusion oncogene. The BCR-ABL1 protein causes constitutive tyrosine kinase activity. While first-generation TKIs are effective for CML, resistance often arises from ABL1 mutations or SRC kinase overexpression. The aim of this study is to identify phytochemicals as potential dual inhibitors of ABL1 and SRC kinases in resistant CML, providing an alternative strategy to overcome the limitations of current TKIs. This study investigates the potential of 1249 phytochemicals from various herbal plants to combat therapy resistance in CML by targeting ABL1 and SRC kinases. It includes a thorough analysis of protein selection, ligand dataset preparation, ADME analysis, molecular docking, and dynamics simulation study, followed by toxicity assessments. Out of 1249 screened phytochemicals, 792 satisfied Lipinski’s rule. These 792 ligands were taken for molecular docking, and two key ligands, 1,3-dibenzylisoquinoline and Artonin J, were obtained. 1,3-Dibenzylisoquinoline exhibited strong binding affinities of −11.2 kcal/mol (ABL1 WT, 4WA9), −8.7 kcal/mol (ABL1 T315I, 4TWP), and −9.5 (SRC WT, 7NG7), −9.4 kcal/mol against (SRC T338M, 3G5D), outperforming the control drugs imatinib and ponatinib in several cases. 1,3-Dibenzylisoquinoline exhibited favorable interactions with suitable ADME/T profiles, whereas Artonin J showed one unfavorable bond and multiple toxicities. 1,3-Dibenzylisoquinoline demonstrates strong potential as a therapeutic candidate for CML, with effective kinase inhibition and a favorable safety profile compared to current TKIs and requires further in-vitro and in-vivo investigations for clinical translation. • Investigated 1249 phytocompounds in chronic leukemia that target ABL and SRC kinase. • 792 phytochemicals from 1249 follows Lipinski's drug-likeness. • Investigation of binding affinity & conformational stability through molecular docking & dynamics simulation study. • 1,3 Dibenzylisoquinoline demonstrated significant binding potential and minimal toxicity.