Computational study to develop new bromodomain-containing protein 9 inhibitors

Bromodomain represents a large family of evolutionary protein modules that bind acetylated lysines. Bromodomain-containing protein 9 (BRD9) plays a role in chromatin remodeling and regulation of transcription. Because of its biological role, there is growing interest in this protein as a potential therapeutic target.

The main task of this work was to identify new potential inhibitors of BRD9 by using an evolution of the classic fragment-based methods. Starting from a crystallographic structure (PDB 5IGN), we built a hit molecule directly inside the active site of the protein. We designed a structure able to interact with the key residues in the binding site and with new unexplored sites. We selected several analogs to use as lead compounds by an extensive and automatic search of the scaffold structure on ZINC databases. We created a combinatorial library of potential inhibitors based on topological information directly in the binding site during a molecular dynamics simulation. We have selected the best inhibitor potential based on binding energy and residence time. Our approach could be tailored to several systems. The main strength of the approach is the speed of the analysis and the accuracy of the results.