Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics.

The human genome encodes three active DNA methyltransferases: DNMT1, DNMT3a, and DNMT3b. DNMT1 is required for the maintenance of DNA methylation patterns during replication in normal and cancer cells and is essential for their proliferation and survival. DNMT3a and DNMT3b are de novo methyltransferases involved in embryonic development and in the establishment of genomic imprints. The analysis of DNA methylation patterns in normal and tumor cells has revealed that many, if not all, human tumors exhibit an altered methylation signature.

Two DNA methyl-transferase receptor-based target-focused libraries offered by OTAVAchemicals are targeted towards DNMT1 and DNMT3b in such a way to minimize cross-reactivity between these two proteins. Virtual screen of Drug-like Green Collection against DNMT3b and DNMT1 structures was validated with a reference set of known DNMT inhibitors obtained from ChemblDB. Final selection of compounds has been made with inspection of active site’s critical structural determinants for ligand binding, docking score cut-off filtering, intermolecular hydrogen bonds with crucial active site’s residues taken from literature reviews and exclusion of predicted DNMT1 and DNMT3b cross-binders. Also, a 3D pharmacophore model consisted of two hydrogen bond donors, two hydrogen bond acceptors and a hydrophobic region has been applied during the selection. 

DNA methyl-transferase DNMT1 receptor-based target-focused library - 368 compounds

DNA methyl-transferase DNMT3b receptor-based target-focused library - 1197 compounds

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