Applied Biophysics for Bromodomain Drug Discovery

The dynamic regulation of epigenetic processes is dictated by the addition, removal, and recognition of posttranslational modifications on proteins and nucleic acids. These processes further regulate how our genetic information is accessed within chromatin. The recognition of acetylated histones by bromodomain modules is one such process that has been significantly evaluated as a promising interaction to disrupt for developing epigenetic therapies. The discovery of such inhibitors has been aided by the application of a wealth of biophysical and computational tools leading to insights into the structural biology of bromodomains and potent inhibitors that are advancing in the clinic. This chapter will first provide a brief historical overview on the discovery and characterization of bromodomains, followed by several of the seminal discoveries of bromodomain inhibitors. The remainder of the chapter will provide descriptions of the experimental and computational tools that are available to scientists interested in biophysical analysis of bromodomain inhibitor discovery for developing new drugs and chemical probes. The field of chemical epigenetics is rapidly expanding, and the goal of this chapter is to help researchers keep abreast of the new methods being used to study this important epigenetic protein domain.