RESCUING DESTABILIZED MUTANT TUMOR SUPPRESSORS
The Karanicolas lab been developing computational tools specifically catered to the shallow surface pockets typical of sites that are not naturally evolved for small-molecule binding. By exploring low-energy fluctuations of the protein surface, we can reveal cryptic druggable pockets - and then use these as the basis for structure-based virtual screening.
MODULATING ANTIBODY ACTIVITY USING CHEMICAL BIOLOGY
We have developed an approach called “chemical rescue of structure” to introduce allosteric control of protein activity through a designed ligand-binding site, and have begun applying it to antibody structures. Briefly, we introduce a pair of adjacent cavity-forming mutations between the variable domains that disrupts their relative orientation, and thus their antigen binding.
PRECISION TARGETING OF THE HUMAN KINOME: BIG DATA, BIG LIBRARIES
The Karanicolas lab has recently developed a comparative modeling approach that allows us to computationally predict – rapidly and with atomic accuracy – the three-dimensional structure of any given inhibitor/kinase pair. We have now begun extending this research in two new directions.
DESIGNING CHEMICAL TOOLS TO INHIBIT RNA-BINDING PROTEINS
We have recently developed a new and unique computational approach for designing inhibitors of a given RBP, starting from its structure in complex with RNA. Briefly, our approach distills the cognate RNA to the functional groups that contribute most of the binding energy to the interaction, and then uses the precise three-dimensional geometry of these groups as a template for structure-based pharmacophore screening.