Comparative Cheminformatic Analysis of Inhibitors of DNA Methyltransferases

Abstract

DNA methylation is an epigenetic mechanism mediated by a family of the enzymes DNA methyltransferases (DNMTs): DNMT1, DNMT3A and DNMT3B. These enzymes are emerging targets for the treatment of cancer and other diseases. Over the past few years several inhibitors of the three enzymes have been reported. Herein, we present a comprehensive chemoinformatic characterization of data sets of inhibitors of DNMT1, DNMT3A and DNMT3B assembled in this work. The compound data sets were analyzed in terms of physicochemical properties, structural fingerprints, and molecular scaffolds. As part of the characterization, a scaffold enrichment analysis was performed as well as visual representation of the chemical space. It was found that inhibitors of DNMT1 are the most diverse covering a broad area of the chemical space. Scaffold diversity analysis showed that inhibitors of DNMT1 and DNMT3A have a larger number of molecular scaffolds as compared to DNMT3B. It was also concluded that for all inhibitors there are molecular scaffolds enriched with active molecules and thus represent promising starting points for additional drug development.