Pharos: Collating protein information to shed light on the druggable genome

Abstract

The ‘druggable genome’ encompasses several protein families, but only a subset of targets within them have attracted significant research attention and thus have information about them publicly available. The Illuminating the Druggable Genome (IDG) program was initiated in 2014, has the goal of developing experimental techniques and a Knowledge Management Center (KMC) that would collect and organize information about protein targets from four families, representing the most common druggable targets with an emphasis on understudied proteins. Here, we describe two resources developed by the KMC: the Target Central Resource Database (TCRD) which collates many heterogeneous gene/protein datasets and Pharos (https://pharos.nih.gov), a multimodal web interface that presents the data from TCRD. We briefly describe the types and sources of data considered by the KMC and then highlight features of the Pharos interface designed to enable intuitive access to the IDG knowledgebase. The aim of Pharos is to encourage ‘serendipitous browsing’, whereby related, relevant information is made easily discoverable. We conclude by describing two use cases that highlight the utility of Pharos and TCRD.

The ChEMBL database in 2017

“…pathway, expression or disease information). ChEMBL data is incorporated into a wide range of other resources including PubChem BioAssay (52), BindingDB (11), CanSAR (53), Open PHACTS (54), Open Targets (55) and the Target Central Resource Database/PHAROS (http://juniper.health.unm.edu/tcrd/, 56), so can also be accessed via these routes. However, since these other resources are different in scope, they do not all incorporate ChEMBL in full (e.g.…”

Novel approaches leading towards peptide GPCR de‐orphanisation

“…Aggregated disease associations for orphan receptors from OpenTargets (Carvalho‐Silva et al, ) highlight the clinical relevance and therapeutic potential across disease areas ( purple ring , darker shading denotes stronger association ). Inner ring: orphan GPCR publication/knowledge scores ( black ) and tool compounds listed on the ChEMBL database ( blue ; Nguyen et al, )…”

Evidence-Based Precision Oncology with the Cancer Targetome

“…However, the promise of precision oncology has been dimmed with the realization that only a small number of genetic variants in cancer are currently actionable with approved drugs [2,5]. Much of the work focused on expanding what is considered to be actionable in cancer genomics has focused on characterizing cancer-associated and driver genes and prioritization of these candidates for therapeutic intervention [6–9]. But any endeavor to expand the actionable space and thereby expand patient treatment options requires that we have a working knowledge of the interactions between drugs and their biological targets .…”

“…The Drug Gene Interaction Database aggregates drug-target annotation across multiple sources, allowing the user to see the parent sources and total literature reference count per drug-target interaction, but it does not currently include binding activity evidence [38]. Other resources that provide experimental binding evidence for target annotations for approved drugs and/or clinical trial drugs include DrugCentral, Pharos, SuperTarget, and STITCH [9,39–41]. The Open Targets is a recently released academic-industry collaborative resource that includes drug-target interaction information, but it is currently more focused on enabling target validation efforts [42].…”

“…used a threshold of 100nM on ChEMBL bioactivity data (across all assay types) to supplement target annotation found in company pipelines and the literature for approved and clinical trial drugs [60]. The Pharos platform, which presents data from the Target Central Resource Database (and uses a Target Development Level scheme to group targets based on level of study and association with small molecule bioactivity), uses bioactivity thresholds based on target family specific cut-offs [9]. …”