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BBB seminar: Richard Alan Engh

Understanding enzyme flexibility is essential for structure based protein kinase inhibitor drug discovery

Richard Alan Engh
Department of Chemistry, University of Tromsø

In just over two decades, structure based protein kinase inhibitor discovery, beginning with trial and error approaches using single targets, has been transformed into a massive research effort, enabling structure and data-driven approaches that even may design target selectivity profiles, using thousands of known inhibitors as starting points.

One priority for current drug discovery efforts is to adapt known compounds to new therapeutic uses, increasingly important as patents expire. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties have the potential to transform kinase inhibitor research away from single, block-buster drug models, and into "personalized" medicine and other niche areas, where also academic groups may specialize. On the other hand, significant barriers for developing such tools exist, including mismatches of data types, of experimental conditions, and of in vitro model systems, and the fundamental problem that ligand binding energies cannot be predicted precisely from structure.

Protein flexibility is behind much of the unpredictability of enzyme-ligand binding energies. This is especially true for protein kinases, because their cell signalling functions, which require strict activity control mechanisms, are modulated by a variety of structural transformations. These include a switch-like "DFG in/out" transformation of the activation loop, movements of the "C" or "PSTAIRE" alpha helix, variations in the relative orientations of the two folding subdomains whose interface creates the ATP binding pocket, and conformational changes of the glycine-rich beta-hairpin turn and double stranded loop that forms one side of the pocket. Although flexibilities hinder predictivity in drug design, they do provide a broad variety of mechanisms for inhibitor selectivity.

Thus, despite their common function to transfer phosphate from ATP to substrate proteins, protein kinases offer many approaches for the design of inhibitors with optimized target selectivity profiles, from monospecific inhibition, to specific sets of targets in polypharmacology approaches. Specific examples from anticancer, antiinflammation, and neuroprotective drug design projects illustrate these points.

Chairperson: Ruth Brenk <ruth.brenk@uib.no>, Department of Biomedicine