Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces

Area of Science:

• Epigenetics and Drug Discovery
• Structural Biology
• Chemical Biology

Background:

• Epigenetic modifications regulate gene expression and are key targets in drug discovery.
• Inhibitor development for epigenetic reader domains faces challenges due to lack of well-defined binding sites.
• Proteins involved in epigenetic regulation often possess multiple domains, suggesting potential for novel inhibition strategies.

Purpose of the Study:

• To investigate the potential of targeting domain-domain interfaces for small-molecule inhibitor design in epigenetics.
• To identify and validate novel binding pockets within multi-domain epigenetic proteins.

Main Methods:

• Computational analysis of X-ray structures using the SiteMap algorithm to identify potential binding sites at domain-domain interfaces.
• Experimental validation through X-ray crystallographic fragment screening.

Main Results:

• SiteMap algorithm successfully identified potential binding sites at domain-domain interfaces of epigenetic proteins.
• A specific inter-domain site in the tandem plant homeodomain-bromodomain of SP100C was computationally identified.
• Experimental fragment screening validated the identified inter-domain site and discovered ligands.

Conclusions:

• Targeting domain-domain interfaces represents a promising strategy for developing small-molecule inhibitors against epigenetic reader domains.
• This approach overcomes limitations of targeting single domains and offers new avenues for epigenetic drug discovery.