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Discovery and development of new drugs and therapeutic agents is greatly aided by knowing the identity of proteins affected by small molecule drugs, the drug targets. Understanding the drug targets is the key factor in development and optimization of drug candidates for high efficacy and low toxicity. Currently, large majority of the small molecule drugs on the market affect a small fraction of potential drug targets of the human proteome. In recent estimates the number of druggable targets is significantly higher, possibly as much as one order of magnitude higher, than the current number of protein targets through which small molecule drugs mediate their effect [1]. With the advancements in genomics and molecular biology, drug development has, over last several decades, largely depended on assessing activity against purified recombinant proteins. However, due to complexities of the cellular environment, presence of different splice variants and posttranslational modifications of the target protein and abundance of other proteins, these in vitro experiments may not predict the effect of drugs in complex in vivo systems. Furthermore the “off targets” effects of small molecule drugs cannot be easily assessed with in vitro experiments. Thus, evaluating phenotypic effect of small molecules using complex, in vivo cellular or animal models, offers a valuable alternative for drug development. In this process known as phenotypic screening small molecules are selected based on their ability to elicit desired phenotype, and only after this stage is completed, the search for drug target begins. This approach has resulted in discovery of majority of first-in-class drugs with novel mechanisms of action [2]. Thus, drug discovery process is seeing a comeback of phenotypic screening. This comeback has been facilitated with development of new tools for discovery of targets for small molecules identified in phenotypic screen.

Chemo Proteomics, a Valuable Tool for Biomarker and Drug Discovery