The 70 kDa heat shock protein plays an important role in cancer and in a number of other diseases associated with protein misfolding. As a result, pharmacological modulation of Hsp70 with small molecules may represent a useful therapeutic approach in these diseases. The discovery of such agents has been hampered by the lack of a full-length crystal structure of human Hsp70. As a result, we have constructed a homology model of hHsp70 protein. An unexplored novel allosteric binding site (Site 1), distinct from the nucleotide-binding site, was identified using SiteMap. Potential ligand/protein interactions were studied using Glide docking and interpretation of binding site resulted in the identification of YK5, the first dual and selective modulator of Hsp70. Taken together, the present study resulted in the discovery of a novel allosteric site (Site 1) and compounds targeting this site. Details about the molecular modeling will be discussed in the poster.

Identification and validation of a novel allosteric pocket on human heat shock protein 70 (Hsp70) homology model for the discovery of Hsp70 inhibitors

243rd National Meeting (2012)

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