Computational Design of PROTAC Molecules Targeting Disruptor of Telomeric Silencing 1-Like (DOT1L) Enzyme for Precision Treatment of Mixed-Lineage Leukemia

Leukemia is a blood cancer that affects the bone marrow and causes a production of abnormal white blood cells. DOT1L is an enzyme that regulates gene expression, cell cycle progression and DNA repair and plays a major role in Mixed-Lineage Leukemia. PROTAC is a molecule that is designed to degrade target proteins in cells. By attaching to DOT1L and E3 Ligase, it helps the body find cancerous cells and destroy the DOT1L using proteasomal degradation. The aim of this research is to design and evaluate PROTAC molecules targeting DOT1L for the treatment of Mixed Lineage Leukemia using computational modeling and docking simulations. We hypothesize that PROTAC-mediated degradation of DOT1L will specifically eliminate oncogenic proteins in Mixed Lineage Leukemia, providing a more targeted and effective therapeutic strategy than conventional chemotherapy. DOT1L and E3 Ligase 3D structure were predicted by using AlphaFold. DOT1L-PROTAC-E3Ligase binding structure was done by HDOCK. The binding energy calculation was done by the PROTAC webserver. The results show that PROTAC mutations M3 and M7 have a stronger binding to both DOT1L and E3ligase. We have also used Micelle and Cyclodextrin to increase the solubility of the PROTAC. Pharmaceutical properties of both M3 and M7 are higher compared to the other mutations. The current research will help in developing a novel treatment method that can be used in multi-lineage leukemia.