What Makes Inhibitors of BET Proteins Bromodomain Selective? A Case Study with a Lead Candidate for Male Contraceptives

Abstract

BET proteins are epigenetic readers made of two bromodomains that regulate gene transcription by interacting with histones. Diseases that may ensue can be fight by inhibiting BET proteins, but the different role and close similarity of the two bromodomains make it difficult devising selective inhibitors. None has been approved as yet. The challenge of bromodomain selectivity has been taken here by going farther than ranking the importance of inhibitor‐protein contacts from distances in the crystal. Assessing inhibitor selectivity was based here, for the first time with BET proteins, on the energy involved in contacts between the inhibitor and amino acids, dissected from computer simulations under physiological‐like conditions. Because of the high relevance of hydrogen bonds, which are not adequately treated by Newtonian molecular dynamics, the strict environment of the inhibitor was treated by first principles, entrusting all other to a classical treatment, in what are termed QM‐MM simulations. In a case study with a lead candidate as male contraceptive it emerged that BD1 selectivity improves markedly by turning from the commonly dominant interaction with ASN to a different BD1‐specific stronger foothold.