A pinboard by
Sarah Riutta

I'm a PhD student at the Medical College of Wisconsin. I want to find smarter ways to treat disease.


Dissecting interactions between two proteins involved in psoriasis disease progression

Psoriasis disease is an autoimmune disorder characterized by inflammation of the epidermal layer of skin. This inflammation is driven by migration of T cells into the epidermis and production of pro-inflammatory cytokines. During active psoriasis disease, the chemokine CCL20 is up-regulated and promotes migration of T cells expressing the chemokine receptor CCR6. Targeting the CCL20/CCR6 interaction interface is an appealing therapeutic target, but structural information about this interaction is lacking. My thesis research investigates the key interactions between these two proteins to help focus future drug discovery efforts.


Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy.

Abstract: The application of NMR in fragment-based lead discovery (FBLD) has quickly developed from a sensitive method for the identification of low-affinity binders to an important tool in the hit-to-lead process. NMR can play a constructive role in the process from identifying those fragments with the best potential toward a biochemically active compound to developing them into molecules with high affinity and selectivity to a given target protein. NMR hit-to-lead involves revising the lead identification process at the beginning of a fragment-based drug discovery project, the primary screen, and also looking toward protein-detected NMR methods in advancing compounds from fragment hit into and through fragment hit-to-lead. With the development of higher sensitivity cold NMR probes, ligand-based NMR methods can be successfully applied to a majority of projects found in a pharmaceutical pipeline. Having matured from the original concepts such as SAR by NMR (Shuker, S. B., Hajduk, P. J., Meadows, R. P., Fesik, S. W. (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science274 (5292), 1531-1534.), projects that base their lead matter on fragment hits are close to or already in the clinic (Woodhead, A. J., Angove, H., Carr, M. G., Chessari, G., Congreve, M., Coyle, J. E., Cosme, J., Graham, B., Day, P. J., Downham, R., Fazal, L., Feltell, R., et al. (2010) discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J. Med. Chem.53, 5956-5969, Chessari, G., and Woodhead, A. J. (2009). From fragment to clinical candidate: A historical perspective. Drug Discov. Today14 (13-14), 668-675.). Generating new ideas toward new binding modes and mechanisms of action as well as new intellectual property will be the standard by which the success of FBLD will need to be measured. A strategy outlining the various steps involved in NMR hit-to-lead is provided. By means of a specific example, the workflow is described to guide the reader through the experimental setup.

Pub.: 05 Mar '11, Pinned: 21 Jun '17