Histone Lysine Methyltransferases-Conformational Dynamics and Selective Inhibitor Design for Chromatin-Modifying Enzymes in Lymphomas and Melanomas
Abstract
The long-term objective of this project is to advance the understanding of the biology, therapeutic potential and availability of small molecule drugs for cancer-implicated histone lysine methyltransferases (HKMTs) EZH2 (lymphoma and melanoma target) and SETDB1 (melanoma target). The immediate objective of this project is to present to the scientific community a number of novel small molecule binding modes and pockets in those protein targets, as well as novel small molecule chemical probe scaffolds to hit them. In this report, I show the preparation and data collection in tens of thousands of molecular dynamics trajectories on the distributed computing system Folding@home, and generation of dynamic models of the conformational ensembles of EZH2 and EED, both in apo, and in-complex form (PRC2 complex). I successfully deployed a semi-automatic Markov state model building pipeline on a pilot model system SETD8, hence creating a well sampled, prototypical Markov state model, from which to seed conformations for this project and extract reaction coordinates for adaptive and enhanced sampling simulation runs. I am continuing to refine the models, while building a small molecule ensemble pocket detection docking free energy calculations pipeline to select candidates for screening.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2018
- Accession Number
- AD1093711
Entities
People
- Rafal Wiewiora
Organizations
- Weill Cornell Medicine