5/23 - Seminar (chem bio): James Wells, UCSF
James Wells - speaker's webpage
Department of Pharmaceutical Chemistry and Cellular & Molecular Biology
University of California at San Francisco
Host: Michael Hecht
Challenging targets for drug discovery
Many targets of biomedical interest do not have useful small molecule starting points. This is especially true for proteins that engage in protein-protein interactions or that may be regulated by allosteric interactions. For these sites, plasticity and conformational adaptability of proteins has begun to reveal new opportunities for drug discovery on targets previously assumed to be undruggable. I will present a site-directed fragment-based discovery approach, disulfide-trapping, that is well-suited to probing these challenging surfaces. Although protein-protein interfaces are generally flat and large, small fragment molecules can be found that bind with much greater ligand efficiency to “hot-spots” and in crevices that protein partners do not exploit. Second, the site-directed nature of disulfide-trapping makes it very useful for exploring allosteric sites that may not be found by typical screening approaches. I’ll present examples where we were able to find both inhibitory and activating allosteric sites, even from the same site. These technologies and the intrinsic adaptability and flexibility of proteins dramatically expand the opportunities for drug discovery at protein-protein interfaces and allosteric sites.