BioChemGRAPH - an integrated knowledge graph to facilitate basic and translational research

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Endogenous small molecules like drugs, sugars, amino acids, and lipids play important roles in regulating complex biological processes. They do so by interacting with macromolecules such as proteins or nucleic acids to facilitate, disrupt or change their function or interaction patterns. The three-dimensional structures of small molecules in complex with macromolecules and the associated biochemical experiments can provide key insights into their function and mode of action. This understanding can support the design of new enzymes or new drug candidates. The Protein Data Bank (PDB) is the single global archive of macromolecular structures and also contains more than 30,000 unique small molecules observed in nearly 120,000 complexes. The ChEMBL database archives biochemical assay data that provides complementary information to understand the biological role of the small molecules. The Cambridge Crystallographic Data Centre (CCDC) manages an archive of over 1 million small molecule crystal structures that can provide insights into small molecules interactions, which can be especially important in the design of new drug molecules. Exponential growth in the scale and diversity of data due to recent technological and scientific advances have transformed life sciences into a data-driven activity, with multidisciplinary teams using data from many sources to drive new innovations in the fields of biotechnology, synthetic biology, agriculture, and human health. A major effort is currently expended by the users to standardise, curate and integrate data from multiple data resources to gain a comprehensive understanding of biological systems. The BioChemGRAPH project aims to establish a collaboration between PDBe, ChEMBL and CCDC to create an easily accessible resource that integrates structural, functional and biochemical annotations of small molecule data into one place. These data will be added into an existing community-driven integration platform, namely PDBe-KB, which already provides an aggregated view of structural and functional annotations for macromolecules in the PDB. Building on PDBe-KB's efforts in the macromolecular community, this project will promote interoperability between small molecule resources by implementing common data standards. The project also aims to improve the findability and accessibility of small molecule annotations via uniform data access mechanisms and develop intuitive web components to visualise these valuable data through web interfaces. It will significantly increase the synergies between structural and biochemical data and will lead to increased understanding of the role of small molecules in biological systems (e.g. enzymatic mechanisms) and translational research in a number of areas, including synthetic biology, target validation, and drug development. Interconnections between targets and small molecules, which currently require manual collation, would be automatically established as part of the proposed project and could help with target validation and potential drug repurposing, highlighting potential cross-reactivity, and side effects. In order to achieve this automated linking, we will build upon and expand UniChem, a service that offers mappings between small molecule entries from numerous data resources. With the help of a readily available integrated resource, we will develop user-friendly web pages aggregating all the data for a given small molecule and relevant macromolecules. Advanced users will also benefit from the expanded programmatic access mechanisms to the integrated data. The new infrastructure will thus help researchers by providing a robust, time-saving mechanism to obtain all relevant small molecule-related data and associated biochemical, structural and functional information on macromolecules.