Abstract
BackgroundThe Open Targets Platform integrates different data sources in order to facilitate identification of potential therapeutic drug targets to treat human diseases. It currently provides evidence for nearly 2.6 million potential target-disease pairs. G-protein coupled receptors are a drug target class of high interest because of the number of successful drugs being developed against them over many years. Here we describe a systematic approach utilizing the Open Targets Platform data to uncover and prioritize potential new disease indications for the G-protein coupled receptors and their ligands.ResultsUtilizing the data available in the Open Targets platform, potential G-protein coupled receptor and endogenous ligand disease association pairs were systematically identified. Intriguing examples such as GPR35 for inflammatory bowel disease and CXCR4 for viral infection are used as illustrations of how a systematic approach can aid in the prioritization of interesting drug discovery hypotheses. Combining evidences for G-protein coupled receptors and their corresponding endogenous peptidergic ligands increases confidence and provides supportive evidence for potential new target-disease hypotheses. Comparing such hypotheses to the global pharma drug discovery pipeline to validate the approach showed that more than 93% of G-protein coupled receptor-disease pairs with a high overall Open Targets score involved receptors with an existing drug discovery program.ConclusionsThe Open Targets gene-disease score can be used to prioritize potential G-protein coupled receptors-indication hypotheses. In addition, availability of multiple different evidence types markedly increases confidence as does combining evidence from known receptor-ligand pairs. Comparing the top-ranked hypotheses to the current global pharma pipeline serves validation of our approach and identifies and prioritizes new therapeutic opportunities.
Highlights
The Open Targets Platform integrates different data sources in order to facilitate identification of potential therapeutic drug targets to treat human diseases
This amounts to approximately 2% of all known protein-coding genes. They are, the largest ‘target’ class of the ‘druggable genome’ representing approximately 19% of the currently available drug targets [2, 3]. They have long played a prominent role in drug discovery [4] – so much so, that as of this writing, 475 United States Food and Drug Administration (FDA) approved drugs act on G-protein-coupled receptor (GPCR) [5]
Distribution of the overall Open Targets score and relationship to individual data types At the time of this analysis the Open Targets Platform integrates fifteen different data sources organized into seven different data types: genetic association, somatic mutations, Ribonucleic acid (RNA) expression, known drug targets, affected molecular pathways, animal models, and text mining [13]
Summary
The Open Targets Platform integrates different data sources in order to facilitate identification of potential therapeutic drug targets to treat human diseases. It currently provides evidence for nearly 2.6 million potential target-disease pairs. There are currently 827 known human G-protein coupled receptors (GPCRs) of which 406 are non-olfactory [1] Together, this amounts to approximately 2% of all known protein-coding genes. This amounts to approximately 2% of all known protein-coding genes They are, the largest ‘target’ class of the ‘druggable genome’ representing approximately 19% of the currently available drug targets [2, 3]. GPCRs have ligand binding sites on the outer cell surface membrane, and potent effects can be
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