Illuminating the druggable genome: Pathways to progress

Abstract

There are ∼4500 genes within the 'druggable genome', the subset of the human genome that expresses proteins able to bind drug-like molecules, yet existing drugs only target a few hundred. A substantial subset of druggable proteins are largely uncharacterized or understudied, with many falling within G protein-coupled receptor (GPCR), ion channel, and kinase protein families. To improve scientific understanding of these three understudied protein families, the US National Institutes of Health launched the Illuminating the Druggable Genome Program. Now, as the program draws to a close, this review will lay out resources developed by the program that are intended to equip the scientific community with the tools necessary to explore previously understudied biology with the potential to rapidly impact human health.

FIGURE 1. Structure and goals of the IDG Consortium.

(a) The IDG program consisted of two phases: a pilot phase and an implementation phase. The goals and outputs for each phase can be seen in the above timeline. (b) The IDG Consortium of the implementation phase is composed of three distinct centers: the DRGCs, responsible for generating and validating new data for IDG-eligible dark targets within the ion channel, GPCR, and kinase protein families; the KMC, responsible for aggregating that knowledge as well as knowledge across the whole human proteome into a database and corresponding knowledge portal; and the RDOC, whose goal is to ensure that the scientific community is aware of resources developed by the program.

FIGURE 2. Example primary search results webpage layout for Tchem protein CATSPER4.

This example of the layout of the Pharos interface is meant to provide the reader with a guide for navigating the results obtained from a protein search. (a) Short summary of information known about CATSPER4, a protein with a TDL of Tchem, including alternative names and symbols as well as an ‘illumination graph’ to visualize what type of data are available. (b) The left-hand column contains multiple fields to explore what is known about the protein in more depth and includes several tools available through Pharos, such as predicted disease and/or viral interactions, GWAS traits, and pathways. (c) The IDG Development Level Summary for CATSPER4, indicating that it satisfies the preceding conditions of Tdark and Tbio and has five known active ligands, designating it as Tchem.

FIGURE 3. Sample of visualization tools available through Pharos (CATSPER4).

This image is meant to provide the reader with a visual representation of the types of resources available in Pharos for proteins of interest. (a) Pathways that a protein is involved in can be explored through the Reactome tool. (b) Alphafold has been incorporated into the Pharos interface, allowing users to see both known and predicted structures of proteins. (c) There are several visualization tools available to explore tissue expression of proteins; these include an anatogram for exploring expression of a protein at the system, organ, or cellular level, and anatomical visuals for analyzing tissue-specific gene expression.

FIGURE 4. Shifts in TDLs for IDG-eligible proteins over time.

(a) Diseases focused on in publications resulting from work completed under IDG pilot project awards. (b) Tdark proteins illuminated during the implementation phase of the IDG Program. Each of the DRGCs began the program with a set number of dark proteins for illumination. The graph shows progress in illuminating these proteins since the initiation of the implementation phase in 2018. For all three protein families, significant numbers of proteins have shifted from Tdark designation to the more illuminated Tbio and Tchem development levels.

FIGURE 5. Overview of publication statistics associated with the IDG Program.

(a) Increase in publications on understudied IDG proteins after initiation of the program (this analysis does not include publications from the IDG Program awardees). Red line denotes the start of the implementation phase of the IDG Program. (b) Number of publications produced by IDG awardees per year (left). Publications, as well as citation counts, have been steadily increasing in each year of the program. (c) The translation of scientific knowledge into clinical studies for the IDG Program; publications are broken down into papers that fall within human-, molecular/cell-, or animal-focused categories. The majority of IDG-published work focuses on understanding understudied proteins at the cellular level or within the context of human disease.

FIGURE 6. Attention toward and patent mentions for publications from IDG Program awardees.

(a) All mentions of IDG publications. This includes news, blog, policy, patent, Twitter, peer review, Weibo, Facebook, Wikipedia, Google+, Reddit, faculty opinion, and video mentions. (b) Number of patents per year that reference IDG publications. Graphs were generated by Altmetric.