Using Structural Biology to Exploit Allosteric and Protein:Protein Interactions in Drug Discovery

Date: Sep 20, 2011
Time: 11:00 – 11:50 AM PDT
Speaker: Alex Burgin, Ph.D.

Abstract: Although traditional structure based drug design has focused on the development of active site inhibitors, considerable efforts are now being devoted to develop small molecule drugs that modulate enzyme activity at allosteric sites.  These allosteric modulators have several important advantages over traditional active site inhibitors.  For example, allosteric modulators can be much more potent than competitive inhibitors when substrate concentrations are high since they do not have to compete with substrate for binding.  In addition, allosteric modulators can often be much more selective than active site inhibitors against enzyme superfamilies with highly conserved active sites.  In this webinar, we will review some of the advantages of allosteric modulators compared to traditional competitive inhibitors using several structurally characterized examples.  In addition, we will provide a description of how structural insights were used to develop the first allosteric modulators of PDE4 and how these small molecules modulate specific protein:protein interactions in vivo.  The important technical aspects of obtaining the first ligand-bound regulatory domain will also be emphasized.  By reviewing several examples of allostery and describing a specific example in some detail (PDE4), we hope to provide a paradigm for how structural biology can enable the discovery of this important class of small molecules.