Development of ligands for bromodomains (BRDs) has expanded our understanding of gene regulation and epigenetic links to disease. These acetylated-lysine ‘reader’ domains are found within larger macromolecules that are involved in gene transcription and degradation. We are interested in TRIM33, which is an E3-ubiquitin ligase, containing a C-terminal BRD and known to play a role in the repair of single-strand breaks in DNA. TRIM33’s implication in certain cancers makes it an interesting therapeutic target, an aspect that can be further explored by developing chemical probes for the BRD.<br/><br/>Several compounds that bound to the BRD of TRIM33 were identified through a high throughput screen, one of which mimics the acetylated lysine residue and has been selected for optimisation. As there is no crystal structure of the TRIM-ligand complex, computational methods were employed to enable structure-based drug design. Molecular dynamics simulations and absolute binding free energies were utilized to increase confidence in ranking binding modes. Following our previous work, the energies of binding-site water molecules were probed with Grand Canonical Monte Carlo (GCMC) calculations. Combining both aspects has led to an improved binding model that fits the experimental SAR and is now being used to yield rational designs for future compounds.

Free-energy calculations to guide bromodomain inhibitor optimization

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.