TCRD and Pharos 2021: mining the human proteome for disease biology

Abstract

In 2014, the National Institutes of Health (NIH) initiated the Illuminating the Druggable Genome (IDG) program to identify and improve our understanding of poorly characterized proteins that can potentially be modulated using small molecules or biologics. Two resources produced from these efforts are: The Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/) and Pharos (https://pharos.nih.gov/), a web interface to browse the TCRD. The ultimate goal of these resources is to highlight and facilitate research into currently understudied proteins, by aggregating a multitude of data sources, and ranking targets based on the amount of data available, and presenting data in machine learning ready format. Since the 2017 release, both TCRD and Pharos have produced two major releases, which have incorporated or expanded an additional 25 data sources. Recently incorporated data types include human and viral-human protein–protein interactions, protein–disease and protein–phenotype associations, and drug-induced gene signatures, among others. These aggregated data have enabled us to generate new visualizations and content sections in Pharos, in order to empower users to find new areas of study in the druggable genome.

TIGA: Target illumination GWAS analytics

“…The explicit goal of the NIH Illuminating the Druggable Genome (IDG) program (Oprea et al , 2018) is to “map the knowledge gaps around proteins encoded by the human genome.” TIGA is fully aligned with this goal, as it evaluates the GWAS evidence for disease (trait) – gene associations. TIGA generates GWAS-centric trait–gene association dataset using an automated, sustainable workflow amenable for integration into the Pharos portal (Nguyen et al , 2017; Sheils et al , 2021). The OpenTargets platform (Koscielny et al , 2017) uses Catalog data and other sources to identify and validate therapeutic targets by aggregating and scoring disease–gene associations for “practicing biological scientists in the pharmaceutical industry and in academia.” In contrast, TIGA is a GWAS Catalog-only application that takes into account cited articles in a simple, interpretable manner.…”

“…TIGA is fully aligned with this goal, as it evaluates the GWAS evidence for disease (trait) -gene associations. TIGA generates GWAS-centric trait-gene association dataset using an automated, sustainable workflow amenable for integration into the Pharos portal (Nguyen et al, 2017;Sheils et al, 2021). The Open Targets platform (Ochoa et al, 2020;Ghoussaini et al, 2020) uses Catalog data and other sources, assisted by supervised machine learning, to identify probable causal genes, and validate therapeutic targets by aggregating and scoring disease-gene associations for "practicing biological scientists in the pharmaceutical industry and in academia."…”

DrugCentral 2021 supports drug discovery and repositioning

“…DrugCentral 2021 contains 669 Tchem , 219 Tbio and 14 Tdark proteins linked to 3859, 607 and 39 bioactivity points, respectively. These proteins are mapped onto the Target Central Resource Database (TCRD) and interfaced with the TCRD portal, Pharos, respectively ( 25 , 26 ).…”

Constitutive G protein coupling profiles of understudied orphan GPCRs

“…Importantly, these constitutive GDP-sensitive interactions corresponded well to known G protein coupling, suggesting that it should be possible to study G protein coupling of orphan GPCRs without using activating ligands. To test this idea we fused Rluc8 to the C terminus of 48 class A orphan receptors, 43 of which are on the most recent list of understudied GPCR targets compiled by the Illuminating the Druggable Genome (IDG) project [21,22]. Receptors were coexpressed together with a Ga subunit and Venus-Gbg in genome-edited HEK 293 cells lacking endogenous Gs/olf, Gq/11 and G12/13 proteins [19].…”