Novel DOT1L ReceptorNatural Inhibitors Involved in Mixed Lineage Leukemia: a Virtual Screening, Molecular Docking and Dynamics Simulation Study

Background: The human protein methyl-transferase DOT1L catalyzes the methylation of histone H3 onlysine 79 (H3K79) at homeobox genes and is also involved in a number of significant processes ranging fromgene expression to DNA-damage response and cell cycle progression. Inhibition of DOT1L activity by shRNAor small-molecule inhibitors has been established to prevent proliferation of various MLL-rearranged leukemiacells in vitro, establishing DOT1L an attractive therapeutic target for mixed lineage leukemia (MLL). Most ofthe drugs currently in use for the MLL treatment are reported to have low efficacy, hence this study focusedon various natural compounds which exhibit minimal toxic effects and high efficacy for the target receptor.Materials and
Methods: Structures of human protein methyl-transferase DOT1L and natural compounddatabases were downloaded from various sources. Virtual screening, molecular docking, dynamics simulationand drug likeness studies were performed for those natural compounds to evaluate and analyze their anti-canceractivity.
Results: The top five screened compounds possessing good binding affinity were identified as potentialhigh affinity inhibitors against DOT1L’s active site. The top ranking molecule amongst the screened ligands had aGlide g-score of -10.940 kcal/mol and Glide e-model score of -86.011 with 5 hydrogen bonds and 12 hydrophobiccontacts. This ligand’s behaviour also showed consistency during the simulation of protein-ligand complex for20000 ps, which is indicative of its stability in the receptor pocket.
Conclusions: The ligand obtained out of thisscreening study can be considered as a potential inhibitor for DOT1L and further can be treated as a lead forthe drug designing pipeline.