DNA methylation which is a covalent chemical modification of DNA catalyzed by DNA methyltransferases (DNMTs) plays a crucial role in epigenetic modification. DNMT inhibition is a promising strategy for the treatment of cancer and other diseases. Docking studies of established DNMT1 inhibitors with the crystal structure of human DNMT1 gave rise to a structure-based pharmacophore model that suggests key interactions of the inhibitors with the catalytic binding site. We also report a chemoinformatic-based approach to explore the potential to identify novel inhibitors in large screening collections of natural products and synthetic commercial libraries. The results of this work highlight the value of rational approaches using structure- and ligand-based approaches for the systematic discovery of novel inhibitors targeting DNMT1.

Systematic discovery and optimization of novel DNMT inhibitors: Structure- and ligand-based approaches

244th National Meeting (2012)

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