Docking of a novel DNA methyltransferase inhibitor identified from high-throughput screening: insights to unveil inhibitors in chemical databases.

Inhibitors of DNA methyltransferase (DNMT) are attractive compounds not only as potential therapeutic agents for the treatment of cancer and other diseases, but also as research tools to investigate the role of DNMTs in epigenetic events. Recent advances in high-throughput screening (HTS) for epigenetic targets and the availability of the first crystallographic structure of human DNMT1 encourage the integration of research strategies to uncover and optimize the activity of DNMT inhibitors. Herein, we present a binding model of a novel small-molecule DNMT1 inhibitor obtained by HTS, recently released in a public database. The docking model is in agreement with key interactions previously identified for established inhibitors using extensive computational studies including molecular dynamics and structure-based pharmacophore modeling. Based on the chemical structure of the novel inhibitor, a sequential computational screening of five chemical databases was performed to identify candidate compounds for testing. Similarity searching followed by molecular docking of chemical databases such as approved drugs, natural products, a DNMT-focused library, and a general screening collection, identified at least 108 molecules with promising DNMT inhibitory activity. The chemical structures of all hit compounds are disclosed to encourage the research community working on epigenetics to test experimentally the enzymatic and demethylating activity in vivo. Five candidate hits are drugs approved for other indications and represent potential starting points of a drug repurposing strategy.