ChEMBL: towards direct deposition of bioassay data.

ChEMBL is a large, open-access bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012, 2014 and 2017 Nucleic Acids Research Database Issues. In the last two years, several important improvements have been made to the database and are described here. These include more robust capture and representation of assay details; a new data deposition system, allowing updating of data sets and deposition of supplementary data; and a completely redesigned web interface, with enhanced search and filtering capabilities.

The ChEMBL database in 2017.

ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 and 2014 Nucleic Acids Research Database Issues. Since then, alongside the continued extraction of data from the medicinal chemistry literature, new sources of bioactivity data have also been added to the database. These include: deposited data sets from neglected disease screening; crop protection data; drug metabolism and disposition data and bioactivity data from patents. A number of improvements and new features have also been incorporated. These include the annotation of assays and targets using ontologies, the inclusion of targets and indications for clinical candidates, addition of metabolic pathways for drugs and calculation of structural alerts. The ChEMBL data can be accessed via a web-interface, RDF distribution, data downloads and RESTful web-services.

A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations.

Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application.

Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.

The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

ChEMBL web services: streamlining access to drug discovery data and utilities.

ChEMBL is now a well-established resource in the fields of drug discovery and medicinal chemistry research. The ChEMBL database curates and stores standardized bioactivity, molecule, target and drug data extracted from multiple sources, including the primary medicinal chemistry literature. Programmatic access to ChEMBL data has been improved by a recent update to the ChEMBL web services (version 2.0.x, https://www.ebi.ac.uk/chembl/api/data/docs), which exposes significantly more data from the underlying database and introduces new functionality. To complement the data-focused services, a utility service (version 1.0.x, https://www.ebi.ac.uk/chembl/api/utils/docs), which provides RESTful access to commonly used cheminformatics methods, has also been concurrently developed. The ChEMBL web services can be used together or independently to build applications and data processing workflows relevant to drug discovery and chemical biology.

myChEMBL: a virtual machine implementation of open data and cheminformatics tools.

UNLABELLED: myChEMBL is a completely open platform, which combines public domain bioactivity data with open source database and cheminformatics technologies. myChEMBL consists of a Linux (Ubuntu) Virtual Machine featuring a PostgreSQL schema with the latest version of the ChEMBL database, as well as the latest RDKit cheminformatics libraries. In addition, a self-contained web interface is available, which can be modified and improved according to user specifications. AVAILABILITY AND IMPLEMENTATION: The VM is available at: ftp://ftp.ebi.ac.uk/pub/databases/chembl/VM/myChEMBL/current. The web interface and web services code is available at: https://github.com/rochoa85/myChEMBL.

Collation and data-mining of literature bioactivity data for drug discovery.

The challenge of translating the huge amount of genomic and biochemical data into new drugs is a costly and challenging task. Historically, there has been comparatively little focus on linking the biochemical and chemical worlds. To address this need, we have developed ChEMBL, an online resource of small-molecule SAR (structure-activity relationship) data, which can be used to support chemical biology, lead discovery and target selection in drug discovery. The database contains the abstracted structures, properties and biological activities for over 700000 distinct compounds and in excess of more than 3 million bioactivity records abstracted from over 40000 publications. Additional public domain resources can be readily integrated into the same data model (e.g. PubChem BioAssay data). The compounds in ChEMBL are largely extracted from the primary medicinal chemistry literature, and are therefore usually 'drug-like' or 'lead-like' small molecules with full experimental context. The data cover a significant fraction of the discovery of modern drugs, and are useful in a wide range of drug design and discovery tasks. In addition to the compound data, ChEMBL also contains information for over 8000 protein, cell line and whole-organism 'targets', with over 4000 of those being proteins linked to their underlying genes. The database is searchable both chemically, using an interactive compound sketch tool, protein sequences, family hierarchies, SMILES strings, compound research codes and key words, and biologically, using a variety of gene identifiers, protein sequence similarity and protein families. The information retrieved can then be readily filtered and downloaded into various formats. ChEMBL can be accessed online at https://www.ebi.ac.uk/chembldb.

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.

An open source chemical structure curation pipeline using RDKit.

BACKGROUND: The ChEMBL database is one of a number of public databases that contain bioactivity data on small molecule compounds curated from diverse sources. Incoming compounds are typically not standardised according to consistent rules. In order to maintain the quality of the final database and to easily compare and integrate data on the same compound from different sources it is necessary for the chemical structures in the database to be appropriately standardised. RESULTS: A chemical curation pipeline has been developed using the open source toolkit RDKit. It comprises three components: a Checker to test the validity of chemical structures and flag any serious errors; a Standardizer which formats compounds according to defined rules and conventions and a GetParent component that removes any salts and solvents from the compound to create its parent. This pipeline has been applied to the latest version of the ChEMBL database as well as uncurated datasets from other sources to test the robustness of the process and to identify common issues in database molecular structures. CONCLUSION: All the components of the structure pipeline have been made freely available for other researchers to use and adapt for their own use. The code is available in a GitHub repository and it can also be accessed via the ChEMBL Beaker webservices. It has been used successfully to standardise the nearly 2 million compounds in the ChEMBL database and the compound validity checker has been used to identify compounds with the most serious issues so that they can be prioritised for manual curation.

Network integration and modelling of dynamic drug responses at multi-omics levels.

Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.

1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3.

A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38alpha and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.

Reply to "Missed opportunities in large scale comparison of QSAR and conformal prediction methods and their applications in drug discovery".

In response to Krstajic's letter to the editor concerning our published paper, we here take the opportunity to reply, to re-iterate that no errors in our work were identified, to provide further details, and to re-emphasise the outputs of our study. Moreover, we highlight that all of the data are freely available for the wider scientific community (including the aforementioned correspondent) to undertake follow-on studies and comparisons.

Large scale comparison of QSAR and conformal prediction methods and their applications in drug discovery.

Structure-activity relationship modelling is frequently used in the early stage of drug discovery to assess the activity of a compound on one or several targets, and can also be used to assess the interaction of compounds with liability targets. QSAR models have been used for these and related applications over many years, with good success. Conformal prediction is a relatively new QSAR approach that provides information on the certainty of a prediction, and so helps in decision-making. However, it is not always clear how best to make use of this additional information. In this article, we describe a case study that directly compares conformal prediction with traditional QSAR methods for large-scale predictions of target-ligand binding. The ChEMBL database was used to extract a data set comprising data from 550 human protein targets with different bioactivity profiles. For each target, a QSAR model and a conformal predictor were trained and their results compared. The models were then evaluated on new data published since the original models were built to simulate a "real world" application. The comparative study highlights the similarities between the two techniques but also some differences that it is important to bear in mind when the methods are used in practical drug discovery applications.

A large-scale dataset of in vivo pharmacology assay results.

ChEMBL is a large-scale, open-access drug discovery resource containing bioactivity information primarily extracted from scientific literature. A substantial dataset of more than 135,000 in vivo assays has been collated as a key resource of animal models for translational medicine within drug discovery. To improve the utility of the in vivo data, an extensive data curation task has been undertaken that allows the assays to be grouped by animal disease model or phenotypic endpoint. The dataset contains previously unavailable information about compounds or drugs tested in animal models and, in conjunction with assay data on protein targets or cell- or tissue- based systems, allows the investigation of the effects of compounds at differing levels of biological complexity. Equally, it enables researchers to identify compounds that have been investigated for a group of disease-, pharmacology- or toxicity-relevant assays.

Comprehensive characterization of the Published Kinase Inhibitor Set.

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3.

The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.