Determination of nucleoside DOT1L inhibitors’ residence times by τRAMD simulations

Human epigenetic enzyme disruptor of telomeric silencing 1-like (DOT1L) is a key drug target for treating acute myeloid leukemia. Several nucleoside and non-nucleoside DOT1L inhibitors have been developed to inhibit its histone methyltransferase activity. Non-mechanism-based nucleoside DOT1L inhibitors have shown good inhibitory activity and high on-target residence times. Previous computational studies have explored the dynamic behavior of this group of molecules on DOT1L to design compounds with enhanced binding affinities. Nevertheless, it is well known that drug-target kinetics also plays a crucial role in the discovery of new drugs. Therefore, we performed τ-Random Acceleration Molecular Dynamics (τRAMD) simulations to estimate the residence times of nucleoside DOT1L inhibitors. The high correlation between the calculated and experimental residence times suggested that the method can reliably estimate the residence time of nucleoside DOT1L inhibitors when modifications are made to those substituents that occupy the buried hydrophobic pocket of the active site, exhibit hydrophobic interactions with F245 or that form H-bonds with D161 and G163. Overall, this study will be a step toward understanding the binding kinetics of nucleoside DOT1L inhibitors for the treatment of acute myeloid leukemia.