Current advances on the development of BET inhibitors: insights from computational methods

Epigenetics was coined almost 70 years ago for the description of heritable phenotype without altering DNA sequences. Research on the field has uncovered significant roles of such mechanisms, that account for the biogenesis of several diseases. Further studies have led the way for drug development which targets epi-enzymes, mainly for cancer treatment. Of the numerous epi-targets involved with histone acetylation, bromodomains have captured the spotlight of drug discovery focused on novel therapies. However, due to high sequence identity, the development of potent and selective inhibitors poses a significant challenge. Herein, we discuss recent computational developments on BET inhibitors and other methods that may be applied for drug discovery in general. As a proof-of-concept, we discuss a virtual screening to identify novel BET inhibitors based on coumarin derivatives. From public data, we identified putative structure-activity relationships of coumarin scaffold and propose R-group modifications for BET selectivity. Results showed that the optimization and design of novel coumarins could be further explored.