BME PhD Prospectus Defense - Christine Yueh

10:00 am on Friday, May 9, 2014
44 Cummington Mall, Room 203
Title: "Large-scale analysis of kinase binding sites and druggability"

Sandor Vajda (Advisor, BME)
Dima Kozakov (BME)
Maxim Frank-Kamenetskii (BME)
Adrian Whitty (Chemistry)

Kinases play an important regulatory role in many physiological processes—such as cell cycle control, metabolic control, and DNA damage response—and are thus of great interest as attractive targets for drug discovery. Most efforts toward building kinase inhibitors have focused on the ATP binding pocket, but the ATP pocket is highly conserved amongst human kinases, causing sufficient selectivity to be difficult to achieve. Other binding pockets, however, are not present within all human kinase families, and thus represent potential targets for developing kinase inhibitors with greater selectivity. Aside from the “DFG-out” pocket, which is the binding site for cancer drug Gleevec (Imatinib), they do not tend to be well-studied, despite the advantages of inhibitors that target these sites. The aims of this project are thus to (1) identify these binding sites through the use of computational mapping, which detects regions disproportionately important to binding called “hot spots”, (2) assess their druggability--which is the likelihood that a small, druglike molecule can bind and thus modulate the protein--by applying conditions based on binding “hot spot” strength and size, and (3) compare druggability results with those from existing experimental data, such as inhibitor assays and ligand-bound structures. These aims will be applied to all kinase structures available in the Protein Data Bank, and the results will be made available as an online resource, the Kinase Druggability Atlas.