Pharmaceuticals are designed to interact with specific targets in humans. But it is also important to understand how they might interact with species which they were not designed to target, both in terms of their use in a range of animal models during testing and their potential entry into the environment following patient use and excretion - and the potential risks that environmental exposure may cause. One question the pharmaceutical industry has always struggled to answer has been “which species are at highest risk?”. The answer to this question lies in the original design of the medicine; knowing which species have drug targets similar to those against which the drug was developed in humans is important to the science both in developing a drug and protecting the environment.
Environmental Protection at AstraZeneca
As we push the boundaries of science and develop new medicines, we must conserve natural resources and ensure our products are environmentally safe at all stages in their life cycle. We strive to manage our environmental impacts across the entire value chain from research, development and production through patient use and final disposal.
For more than 20 years AstraZeneca has collaborated with leading environmental scientist Professor Charles Tyler at the University of Exeter to understand the environmental risks of medicines. In this latest collaboration, Bas Verbruggen and Lina Gunnarsson pulled together disparate databases into one user friendly application, www.ECOdrug.org. The concept is to take the known drug protein target, and then examine three different genome databases to identify which organisms these targets also exist in. All organisms whose cells have a nucleus (e.g. fungi, algae, plants and all animals) are classed as eukaryotes, and currently there are 656 eukaryotic genome sequences available. The application does this comparison almost instantly across these genomes and provides a detailed breakdown of where the drug targets appear to exist, and importantly where they don’t. It even produces a cool info-graphic summary of a stylised ‘tree of life’ to help our scientists quickly spot differences. Another layer to the application is that we can now search using the names of medicines available from DrugBank, and again see which species may or may not have the targets for all those drugs that are already on the market (so called established drugs).
Making this tool publicly available supports industrial, academic and regulatory scientists in assessing and managing the risks associated with pharmaceuticals in the environment. This tool represents a new, fantastic first port of call for a new compound to be checked against an existing drug target. In seconds, we can see which types of species may be most vulnerable to the drug, looking across multiple modes of action in primary pharmacology (studying the intended drug-related effects on enzymes, receptors or other targets) and secondary pharmacology (evaluating the potential off-target or unintentional effects of a drug). Previously this would have taken several days. To develop better approaches to understanding the risk of pharmaceuticals to the environment AstraZeneca have been playing a leading role in supporting a European Innovative Medicines Initiative (IMI). The initiative ‘Intelligence-led Assessment of Pharmaceuticals in the Environment’ (iPiE) is a consortium with 12 other pharmaceutical companies, as well as nine Universities, research organisations, public bodies, non-profit groups researchers and three SME companies. iPiE is not only looking to better protect the environment from established drugs that lack full environmental datasets, but also work towards developing drugs more effectively
Pharmaceuticals cannot yet be developed without using animals, but a tool such as this application might help scientists choose to conduct their initial investigations in animals other than mammals. Fish offer one such exciting potential to reduce the number of mammals in developing new drugs, and Prof Tyler’s group have previously developed effective models in zebrafish that help to make decisions for our industry. We hope that ECOdrug will help scientists both in industry and academia work towards more effective selection of their test species. We also believe that the tool can be used to generate testable hypotheses to better understand the specificity of how drugs work. Please try the application at www.ECOdrug.org or read the paper at:
Bas Verbruggen, Lina Gunnarsson, Erik Kristansson, Tobias Österlund, Stewart F. Owen, Jason R. Snape and Charles R. Tyler (2017). ECOdrug: a database connecting drugs and conservation of their targets across species. Nucleic Acids Research gkx1024, https://doi.org/10.1093/nar/gkx1024
We thank our collaborators at University of Exeter and support from colleagues at Chalmers University of Technology and University of Gothenburg in developing the application. We also thank our Innovate UK, (NC3Rs funded project number 102519 ‘Virtual Fish EcoToxicology Laboratory’) collaborators at SimOmics Ltd for hosting the application. The work conducted is also supported by the Innovative Medicines Initiative Joint Undertaking under Intelligent Assessment of Pharmaceuticals grant agreement n° 115735, with a financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution. The manuscript is available at Nucleic Acid Research (https://academic.oup.com/nar/article/4616868), and the application at www.ECOdrug.org
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