Abstract
Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.
Highlights
Genetic information is contained in chromosomes which are made of chromatin, principally a combination of DNA and his-[b] Prof
Structures containing multiple epigenetic domains provide us with an opportunity to study sites formed at the domain–domain interfaces, and investigate whether these sites are suitable for ligand binding
Developing inhibitors of epigenetic proteins is of growing interest in the quest for new treatments for diseases such as cancer and inflammation
Summary
Genetic information is contained in chromosomes which are made of chromatin, principally a combination of DNA and his-. As well as the development of inhibitors for pharmaceutical use, there have been a number of inhibitors designed to be used as chemical probes.[28,29] These are tool compounds with proven in cell target engagement and suitable selectivity and potency that can be used for target investigation and validation experiments (Figure 2) Despite these successes, there are still many families of protein domains involved in reading, writing, or erasing histone tail modifications with very poor inhibitor coverage. There are still many families of protein domains involved in reading, writing, or erasing histone tail modifications with very poor inhibitor coverage Of these many are predicted to be targets with intrinsically low ligandability.[30] A study by Santiago et al.[31] suggested that of methyllysine readers, MBT domains, Tudor domains, and PHDs are inherently less “ligandable” than other epigenetic reader domains. Structures containing multiple epigenetic domains provide us with an opportunity to study sites formed at the domain–domain interfaces, and investigate whether these sites are suitable for ligand binding
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