Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

•A hierarchical docking-based virtual screening combined with molecular dynamic simulation was applied in DOT1L inhibitor discovery.•The key residue contributing the most to the binding of EPZ5676 to the DOT1L protein was identified.•The calculations for the binding free energy were accomplished by using the MM/PBSA method in GROMACS.•Phenoxyacetamide-based scaffold is promising for developing novel DOT1L inhibitors.•The amide moiety of phenoxyacetamide-based scaffold played a crucial role in anchoring the molecule into the DOT1L pocket.