This case study is centered in the discovery of new hits against DNMT. Automated de novo design was employed for the proposal of compounds. We hypothesized that de novo design could lead to molecules that expand the epigenetic-relevant chemical space, due to the expected novelty of the compounds. We selected alvaBuilder (Alvascience, alvaBuilder (software for de novo molecular design) version 1.0.6, 2021, ), a ligand-based de novo design program, to construct the molecules. This software selects fragments as construction blocks and incorporates a genetic algorithm to optimize the search of suitable compounds. To create the fragments and linkers the user has to select a database of entire molecules. The user enters data to create the training set, the molecules are then fragmented into ring systems, linkers, and lateral chains. This approach allows taking advantage of bioactivity data since active modulators could constitute the training set.