Histone methyltransferases are a class of enzymes that covalently modify histone proteins via methylation of lysine or arginine residues. These epigenetic modifiers have been recognized as significant contributors to both normal development and disease. The lysine methyltransferases DOT1L and EZH2 belong to this class of enzymes and have been found to play important roles in leukemogenic processes.
Studies performed in silico, such as molecular dynamics (MD) simulations and docking studies, have been advantageous in understanding drug interactions with the DOT1L binding site. In particular, MD simulations have revealed significant rearrangement of the binding and activation loops of DOT1L as well as stabilization of these loops upon binding to competitive inhibitors. These efforts in computational drug design have proved useful in the identification of potential DOT1L inhibitors.
In addition, the use of structural alignment tools has enabled the generation of an EZH2 model using selected homologous proteins as templates. With a model of EZH2 we have been able to gain knowledge regarding the binding mode of the S-adenosyl methionine cofactor and we hope that this knowledge will enable us to predict the binding modes of other potential inhibitors of EZH2. Through the synergistic combination of in silico drug design, organic synthesis, and biochemical assays, these modeling efforts will help guide the chemical syntheses of inhibitors with improved potency and specificity.
PROJECT: Inhibition of Rogue Methyltransferases: DOT1L and EZH2 in Cancer
Mentors: Jason Marineau and Jay Bradner, Cancer Program
"As a member of the Broad Summer Research Program in Genomics, I have encountered first-hand the power of genomic approaches to the treatment of disease, and I cannot imagine conducting any other type of research. Knowing that my findings may later translate into much-needed drugs has helped me keep things in perspective…this research matters."