Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations
Bromodomain and extra-terminal domain (BET) proteins are key regulators of epigenetic processes and are implicated in various diseases, making them attractive therapeutic targets. BET proteins contain two distinct bromodomains—BD1 and BD2—and selectively targeting one over the other may yield different therapeutic outcomes compared to pan-BET inhibition. However, the molecular basis for selective inhibition remains poorly understood and requires investigation at the atomic level.
This study explores the selective inhibition of BD2 using pyrrolopyridone analogues, comparing the pan-BET inhibitor ABBV-075 with the BD2-selective inhibitor ABBV-744. Through molecular dynamics simulations and binding free energy calculations, the study systematically evaluates how pyrrolopyridone analogues achieve BD2 selectivity. Key amino acid interactions that differ between BRD4-BD1 and BRD4-BD2 complexes were identified, including the pairs I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432.
The pyrrolopyridone analogues were categorized into five structural regions based on their contributions to BD2 selectivity. Among these, the R3 and R5 regions were found to play a critical role and are promising targets for chemical modification to enhance BD2 selectivity. These insights provide a structural framework for the rational design of novel BD2-selective inhibitors based on the pyrrolopyridone scaffold.