discovery of phytochemical-based modulators of fms-like tyrosine kinase-3 (flt3) by hierarchical multistep docking and integrated molecular dynamic simulation for treatment of acute myeloid leukemia

Flt3 aberrations contribute significantly to aml progression by promoting cell proliferation and apoptosis resistance. given the limitations of current inhibitors, novel small-molecule flt3 inhibitors are urgently needed. to tackle this, a computational strategy integrating multistep docking, drug-likeness screening, and md simulations was employed. in this study, a structure-based virtual screening of 23,740 phytochemicals from the npact and phytohub databases was conducted through a hierarchical docking workflow, along with drug-likeness evaluation and md simulations. based on molecular docking and drug-likeness assessments, two lead phub000383 and phub000378 emerged as the most promising flt3 inhibitors, exhibiting high docking scores (phub000383 = -12.968 kcal/mol; phub000378 = -12.137 kcal/mol) and favorable drug-like properties. both compounds demonstrated strong interactions with key flt3 kinase residues, including glu692, cys694, and phe830, which are critical for flt3 activity regulation. to further validate their stability and binding efficiency, 100 ns md simulations were performed, analyzing rmsd, rmsf, and hydrogen bonding interactions. the simulations confirmed that both compounds maintained stable binding within the flt3 active site, exhibited minimal structural fluctuations, and formed persistent interactions with essential residues. these results emphasize phub000383 and phub000378 as promising candidates for developing next-generation flt3 inhibitors, paving the way for further experimental validation and optimization in aml therapy.