Pharos and TCRD : Informatics Tools for Illuminating Dark Targets

The Illuminating the Druggable Genome (IDG) program, a National Institutes of Health Common Fund Program, started in 2013 to improve our understanding of understudied protein families. Outcomes of this program include the Target Central Resource Database (TCRD), a relational database that aggregates and harmonizes a vast array of knowledge sources for drug target data, and Pharos, an interactive web-based tool that enables users to interact with and analyze TCRD data. This chapter provides an overview of the data sources that comprise TCRD and highlights various methods and specific use cases by which users can interact with the TCRD through Pharos. TCRD aggregates annotations and information on 339,220 ligands, 13,704 diseases, and 20,412 targets, which are collected and aggregated from 79 sources. One key feature of TCRD is the definition of four target development levels (TDLs): Tdark, Tclin, Tbio, and Tchem, which describe the level and types of information known for each target in the resource. Beyond displaying the rich TCRD data, Pharos produces interactive visualizations that enable users to view high-level trends in the data (heat maps) and explore common combinations of values in the dataset (UpSet plots). Users can also perform enrichment calculations for a population that can tell users which values are overrepresented, such as which associated diseases are overrepresented in a list of targets or which target classes are overrepresented in a list of active ligands. Users can search and browse data using various types of inputs, including but not limited to target sequences, biological pathways, ligand structures, names, common IDs of targets, drugs, or diseases. Within Pharos, different functionalities can be used to address real-world scientific problems, as shown in use-case scenarios. These include generating hypotheses for the role of a “dark” target (with virtually no known information) and predicting potential targets and target families for a novel chemical compound.