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.

Dot1-like protein (DOT1L) is a histone methyltransferase that has become a novel and promising target for acute leukemias bearing mixed lineage leukemia (MLL) gene rearrangements. In this study, a hierarchical docking-based virtual screening combined with molecular dynamic (MD) simulation was performed to identify DOT1L inhibitors with novel scaffolds. Consequently, 8 top-ranked hits were eventually identified and were further subjected to MD simulation. It was indicated that all hits could reach equilibrium with DOT1L in the MD simulation and further binding free energy calculations suggested that phenoxyacetamide-derived hits such as L01, L03, L04 and L05 exhibited remarkably higher binding affinity compared to other hits. Among them, L03 showed both the lowest glide score (−12.281) and the most favorable binding free energy (−303.9 +/− 16.5 kJ/mol), thereby making it a promising lead for further optimization.

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