Standard high-throughput screening (HTS) methods do not allow targeting of specific sites on a protein. We are screening for both inhibitors and activators using a novel site-directed chemical biology technology called disulfide trapping. We are using this approach to determine the roles of specific inflammatory caspases with selective inhibitors, and to study activation of kinases in proliferation and apoptosis pathways with allosteric activators. With this technology, we can trap allosteric states so that they may be studied by biophysical and mutational means.

In collaboration with Dr. Michelle Arkin and her group in the Small Molecule Discovery Center (SMDC), we are also developing high through-put Surface Plasmon Resonance (SPR) technology for fragment screening. These two fragment screening technologies allow us the potential to tackle challenging protein-protein interaction surface targets and allosteric sites. These discovery technologies will help us learn some of the “rules” for how one might more systematically discover compounds that bind these sites. We hope to unlock these challenging target classes for drug discovery.