While the definition and number of proteins considered "druggable" is a matter of significant debate, only a small fraction of the proteome (207 proteins) is currently targeted by FDA approved drugs. What is more, only 11% of proteins known to be involved in genetic disease are currently targeted by small molecules. FDA approved small molecule therapeutics, as well as protein-binding small molecules developed in industry and academia, primarily target G-protein coupled receptors (GPCRs), nuclear receptors, ion channels, and enzymes (Fig 1). Each of these protein classes contain well-defined pockets that are well-suited to bind a small molecule, and often bind a naturally produced small molecule, The expansion of small molecule drug discovery to extended protein surfaces lacking well-defined binding pockets, and protein-protein interactions continues to be a significant challenge.



Researchers in The McNaughton Group examine the utility of novel synthetic structures well-suited to bind targeted protein surfaces, and inhibit protein-protein interactions involving targeted protein surfaces. Once synthetic methods are identified that make possible the concise synthesis of functionally diverse molecules we design, students prepare combinatorial libraries centered on a favored chemical architecture, and screen these chemical libraries for affinity to a targeted protein (Fig 2). Molecules capable of binding a targeted protein surface, and inhibiting targeted protein-protein interactions in vitro will be examined in vivo using various molecular biology and cellular biology-based methods. Because the protein surfaces and protein-protein interfaces we target have largely been precluded using "standard" small molecules, the compounds we synthesize in the course of our basic science efforts may point the way to a new drug discovery strategy.