In the last years the study of histone post-translational modifications (PTMs) marked an extraordinary progression and a great number of epigenetic modifications has been identified and associated to different fundamental biological processes and pathological conditions. Consistently, several drug discovery programs aimed to devise small-molecules able to pharmacologically modulate epigenetic enzymes have been initiated. In this framework, computer-aided approaches spanning from ligand to structure-based methods promise to play an essential role to speed-up the identification of new chemical entities.Herein we provide an overview of molecular design approaches to target protein lysine methyltransferases (PKMT), which are a group of histone-modifying enzymes that emerged recently as important targets for cancer therapy. We will present a typical computer-aided approach to search for novel inhibitors of SMYD3, a PKMT found to be upregulated in colorectal cancer cells and tissues. Results of in vitro and cell-based assays demonstrate that small-molecules identified with in silico techniques can modulate the activity of SMYD3, thus supporting  the usage of computational approaches as a valuable set of tools for the early-stage identification of new epihits.

Molecular design approaches to target histone methyltransferases

248th National Meeting (2014)

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