Although in epigenetic drug discovery de novo design has been used to identify inhibitors of a bromodomain and other epigenetic targets, such technique has been reported scarcely for designing DNMT inhibitors . Recently, ligand-based de novo design based on compounds with reported activity for DNMT1 and a diverse subset of screening compounds were used to generate novel candidate DNMT1 inhibitors with drug-like properties. Then, the compounds designed de novo were used as reference for fingerprint-based similarity searching in a commercial epigenetic-focused library. The most similar compounds were acquired and tested in an enzymatic inhibition assay, identifying a DNMT1 inhibitor (F447-0397) with a novel chemical scaffold and an enzymatic inhibitory concentration in the micromolar range (Figure ) . The identification of F447-0397 as an inhibitor of DNMT1, inspired by de novo design, is the first approach to the potential of such drug designing approaches to identify novel active molecules with DNMT1 inhibitory activity. Also, recently Lanka et al. implemented a multi-step virtual screening involving docking a fragment library to yield two potential active compounds with DNMT1 . To further explore the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1, herein we discuss a critical assessment of ligand-and structure-based de novo design approaches.