Moving Targets: Monitoring Target Trends in Drug Discovery by Mapping Targets, GO Terms, and Diseases

Abstract

AbstractDrug Discovery is a lengthy and costly process and has faced a period of declining productivity within the last two decades. As a consequence, integrative data-driven approaches are nowadays on the rise in pharmaceutical research, making use of an inter-connected (network) view on diseases. In addition, evidence-based decisions are alleviated by studying the time evolution of innovation trends in drug discovery.In this paper a new approach leveraging data mining and data integration for inspecting target innovation trends protein family-wise is presented. The study highlights protein families which are receiving emerging interest in the drug discovery community (mainly kinases and G protein coupled receptors) and those with areas of interest in target space that have just emerged in the scientific literature (mainly kinases and transporters) highlighting novel opportunities for drug intervention.In order to delineate the evolution of target-driven research interest from a biological perspective, trends in biological process annotations from Gene Ontology (GO) and disease annotations from DisGeNet for major target families are captured. The analysis reveals an increasing interest in targets related to immune system processes, and a recurrent trend for targets involved in circulatory system processes. At the level of disease annotations, targets associated to e.g., cancer-related pathologies as well as to intellectual disability and schizophrenia are increasingly investigated nowadays.Can this knowledge be used to study the “movement of targets” in a network view and unravel new links between diseases and biological processes? We tackled this question by creating dynamic network representations considering data from different time periods. The dynamic network for immune system process-associated targets suggest that e.g. breast cancer as well as schizophrenia are linked to the same targets (cannabinoid receptor CB2 and VEGFR2) thus suggesting similar treatment options which could be confirmed by literature search. The methodology has the potential to identify other drug repurposing candidates and enables researchers to capture trends in research attention in target space at an early stage.The KNIME workflows and R scripts used in this study are publicly available fromhttps://github.com/BZdrazil/Moving_Targets.Author summaryIn this study we have investigated target innovation in drug discovery over a period of 22 years (1995-2016) by extracting time trends of research interest (as published in the scientific literature and stored in the ChEMBL database) in certain protein classes inspecting different measures (numbers of pharmacological measurements, targets, papers, and drugs). Focusing on the most relevant protein classes in drug discovery (G protein-coupled receptors, kinases, ion channels, nuclear receptors, proteases, and transporters), we further linked single targets to Gene Ontology (GO) biological process annotations and inspected steep increasing or decreasing trends of GO annotations within target families over time. We also tracked trends in disease annotations from DisGeNET by filtering out diseases linked to targets with emerging trends in research interest. Finally, targets, GO terms, and diseases are interconnected in network representations and shifts in research foci are investigated over time. This new methodology which utilizes data mapping and data analysis can be used to explore trends in research attention target family-wise, to uncover previously unknown links between diseases and biological processes and to identify potential candidates for drug repurposing.