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

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BioChemGRAPH will develop and sustain an automated process to integrate information for the common set of small molecules from three well maintained and curated core data archives: structures of >30,000 unique small molecules observed in complex with macromolecules from the Protein Data Bank (PDB), small molecule crystal structures from the Cambridge Structural Database (CSD) and associated biochemical assay and target information from ChEMBL. These data will be integrated into the PDBe-KB data resource, a community-driven effort that integrates structural and functional annotations for macromolecules from >20 international data resources.

To achieve this objective, we will build upon and expand UniChem, a service that offers mappings between entries describing small molecules present in numerous data resources. We will map the target information between ChEMBL and the PDB by using UniProtKB accessions cross-referenced in each resource. The project will implement common data standards for the exchange of annotations and will improve findability and accessibility via uniform data access mechanisms (RESTful API and FTP), and via intuitive web components to visualise the data. With the help of this readily available integrated resource, we will develop user-friendly web interfaces aggregating all the data for a given small molecule and its macromolecular binding partners. BioChemGRAPH will thus address a key data integration challenge by developing a robust, time-saving mechanism to obtain all small molecule-related data and associated biochemical, structural and functional information on macromolecules, facilitating increased understanding of the role of small molecules in biological systems (e.g. enzymatic mechanisms) and translational research in a broad range of fields, including synthetic biology, target validation and drug development.

Integrating data from a large number of resources is a challenging but essential task in the new era of data-driven biology. However, keeping track of the increasing number of individual data resources, their curation practices, policies and data formats is nearly an impossible task. Core data resources are uniquely positioned to bring together the growing community of data providers to agree common data exchange standards and thus facilitate the creation of integrated resources with robust data access mechanisms, offering potential time-saving to users. PDBe-KB is one such resource that brings together >20 resources from the Structural Bioinformatics community, including MetalPDB, MCSA and 3DLigandSite, which provide functional annotations for structures in the PDB.

The BioChemGRAPH project will deliver an integrative data resource that will serve as a central repository for structural, functional and biochemical annotations for the common set of small molecular compounds (e.g. drugs, cofactors, inhibitors) and associated target information contained in the PDB, ChEMBL and CSD archives. The integration efforts will not only enrich the information already available in these resources, but also make it more accessible to the broader scientific user community and achieve further impact by combining it with annotations contributed to PDBe-KB. The focus of this work was identified as a clear priority based on feedback from our users through surveys and interviews. The survey received 113 responses from academia (63%) and industry (37%) and guided the definition of needs that will be addressed by this proposal. In particular, the resource will enable users to answer scientific questions that were highlighted in the survey, such as (1) are there annotations explaining the biological role of a particular ligand; (2) are there other small molecules that have the same scaffold or fragments, or bind in similar binding pockets; (3) where are the functional groups of a small molecule based on the statistics of observed atomic-level interactions of the ligand; and (4) which fragment hotspots overlay with the small molecule of interest.

As evident from the support letters, BioChemGRAPH will not only benefit the academic research community but will also provide valuable support for small and medium-sized enterprises and large pharmaceutical companies. The integrated knowledge graph will support a broad range of research areas, e.g. groups studying microbial resistance, rare diseases, drug design or target validation could more easily conduct comparative studies and transfer of structural, functional and interaction-specific annotations between similar small molecules. The resource will also serve as a valuable research tool to investigate the effects of genetic variation, drug resistance, drug repurposing efforts, as well as understanding enzymatic mechanisms at the molecular level, designing synthetic enzymes and other translational research goals. It will enable explorative analyses based on structural similarity, the commonality of scaffolds, fragments or binding pockets. It will also significantly help initiatives like Open Targets and the Illuminating the Druggable Genome project by providing rich data sets in a standardised and interoperable format.

BioChemGRAPH will also deliver a common library of data visualisation tools that will expose the collated data in a uniform manner and lower the barrier to accessing bioactivity and structural data for small molecules. This open source library will potentially standardise visualisation tools for displaying small molecule-related annotations for all relevant data resources. These visualisation tools will also be used to enhance the aggregated views of proteins, effectively linking the small molecule and macromolecule-specific web interfaces.