Defining New Biological and Chemical Targets With Diazirines

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Medicinal chemistry involves using molecules (drugs) to perturb biological systems. This mostly happens through formation of transient small-molecule-protein complexes, where a drug strongly and selectively binds to its protein target(s). The ability to predictably form association complexes between disease-relevant proteins and drug molecules underpins modern medicine, but identifying such complexes for the first time (i.e. discovering new protein binding pockets whose function can be regulated with drug-like small molecules or probes) has historically been done haphazardly, through target-identification campaigns with molecules of known phenotype or through high-throughput screens with pre-validated protein targets. Because of this, fewer than 500 of the proteins encoded by the 20,000 genes in our genome have approved drugs that selectively target them.1 Thousands of additional, medically relevant proteins cannot be controlled with existing small-molecule therapeutics.2 One of the foundational goals of chemical biology is to solve this limitation by identifying a small-molecule regulator for every member of the human proteome.2,3 To meet this grand challenge, our proposed research program will exploit diazirine-enabled complex molecules to search for protein binding partners at the same time as we exploit diazirine-enabled proteins to prospect for small molecule ligands. In a marked departure from established protocols, we will do so without any requirement for our molecules of interest to possess known phenotypic activity. Instead, we posit that every molecule possessing "drug-like" characteristics and a sufficient degree of molecular complexity will have a suite of proteins to which it binds most strongly. We likewise assert that the identification of small-molecule ligands for hypothesized protein pockets is a valuable undertaking that is likely to lead to new scientific understanding, even when that pocket does not have any known regulatory function. Of course, when new regulatory pockets are identified in disease-relevant proteins, these will have immediate utility for drug development. Our research will thus lead directly to the annotation of new biological targets for medicinal chemistry, and will simultaneously deliver new lead compounds that bind to those targets-setting the stage for multiple future collaborative drug discovery projects. This program represents a bold new direction for our group, yet builds upon expertise in organic synthesis, complex molecule characterization, target identification, chemical biology, and diazirine chemistry acquired by our team over the past 15 years. At the same time the research will allow us to develop new skills in proteomics, and in the site-specific incorporation of noncanonical amino acids. The program will provide a fertile training ground for highly qualified personnel, allowing my lab to build upon our considerable record of accomplishment mentoring and teaching successful scientists.