Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Plucking the High Hanging Fruit: A Systematic Approach for Targeting Protein Interfaces
Development of specific ligands for protein targets that help decode the complexities of protein-protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein-protein interactions remains a challenge for chemical biologists. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these domains we can modulate the function of a particular protein with metabolically stable synthetic molecules.(Raj et al., 2013) This presentation will discuss computational approaches(Bullock et al., 2011; Jochim and Arora, 2010) to identify targetable interfaces along with synthetic methods(Patgiri et al., 2008; Tosovska and Arora, 2010) to develop protein domain mimics (PDMs) as modulators of intracellular protein-protein interactions.(Henchey et al., 2010; Patgiri et al., 2011).
This research has been supported by NSF CHE-1151554 and NIH (GM073943)
Henchey, L.K., Kushal, S., Dubey, R., Chapman, R.N., Olenyuk, B.Z., and Arora, P.S. (2010). Inhibition of Hypoxia Inducible Factor 1–Transcription Coactivator Interaction by a Hydrogen Bond Surrogate Alpha-Helix. J Am Chem Soc 132, 941-943.
Jochim, A.L., and Arora, P.S. (2010). Systematic Analysis of Helical Protein Interfaces Reveals Targets for Synthetic Inhibitors. ACS Chem Biol 5, 919-923.
Patgiri, A., Jochim, A.L., and Arora, P.S. (2008). A hydrogen bond surrogate approach for stabilization of short peptide sequences in alpha-helical conformation. Acc Chem Res 41, 1289-1300.
Patgiri, A., Yadav, K.K., Arora, P.S., and Bar-Sagi, D. (2011). An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol 7, 585-587.
Raj, M., Bullock, B.N., and Arora, P.S. (2013). Plucking the high hanging fruit: A systematic approach for targeting protein-protein interactions. Bioorg Med Chem 21, Online article.
Tosovska, P., and Arora, P.S. (2010). Oligooxopiperazines as Nonpeptidic Alpha-Helix Mimetics. Org Lett 12, 1588-1591.
Paramjit S. Arora
Department of Chemistry