The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods.

ChEMBL (https://www.ebi.ac.uk/chembl/) is a manually curated, high-quality, large-scale, open, FAIR and Global Core Biodata Resource of bioactive molecules with drug-like properties, previously described in the 2012, 2014, 2017 and 2019 Nucleic Acids Research Database Issues. Since its introduction in 2009, ChEMBL's content has changed dramatically in size and diversity of data types. Through incorporation of multiple new datasets from depositors since the 2019 update, ChEMBL now contains slightly more bioactivity data from deposited data vs data extracted from literature. In collaboration with the EUbOPEN consortium, chemical probe data is now regularly deposited into ChEMBL. Release 27 made curated data available for compounds screened for potential anti-SARS-CoV-2 activity from several large-scale drug repurposing screens. In addition, new patent bioactivity data have been added to the latest ChEMBL releases, and various new features have been incorporated, including a Natural Product likeness score, updated flags for Natural Products, a new flag for Chemical Probes, and the initial annotation of the action type for ∼270 000 bioactivity measurements.

Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Observation of a Nuclear Recoil Peak at the 100 eV Scale Induced by Neutron Capture.

Coherent elastic neutrino-nucleus scattering and low-mass dark matter detectors rely crucially on the understanding of their response to nuclear recoils. We report the first observation of a nuclear recoil peak at around 112 eV induced by neutron capture. The measurement was performed with a CaWO_{4} cryogenic detector from the NUCLEUS experiment exposed to a ^{252}Cf source placed in a compact moderator. We identify the expected peak structure from the single-γ de-excitation of ^{183}W with 3σ and its origin by neutron capture with 6σ significance. This result demonstrates a new method for precise, in situ, and nonintrusive calibration of low-threshold experiments.

Towards an automated data cleaning with deep learning in CRESST.

The CRESST experiment employs cryogenic calorimeters for the sensitive measurement of nuclear recoils induced by dark matter particles. The recorded signals need to undergo a careful cleaning process to avoid wrongly reconstructed recoil energies caused by pile-up and read-out artefacts. We frame this process as a time series classification task and propose to automate it with neural networks. With a data set of over one million labeled records from 68 detectors, recorded between 2013 and 2019 by CRESST, we test the capability of four commonly used neural network architectures to learn the data cleaning task. Our best performing model achieves a balanced accuracy of 0.932 on our test set. We show on an exemplary detector that about half of the wrongly predicted events are in fact wrongly labeled events, and a large share of the remaining ones have a context-dependent ground truth. We furthermore evaluate the recall and selectivity of our classifiers with simulated data. The results confirm that the trained classifiers are well suited for the data cleaning task.

Secular equilibrium assessment in a CaWO4 target crystal from the dark matter experiment CRESST using Bayesian likelihood normalisation.

CRESST is a leading direct detection sub-GeVc-2 dark matter experiment. During its second phase, cryogenic bolometers were used to detect nuclear recoils off the CaWO4 target crystal nuclei. The previously established electromagnetic background model relies on Secular Equilibrium (SE) assumptions. In this work, a validation of SE is attempted by comparing two likelihood-based normalisation results using a recently developed spectral template normalisation method based on Bayesian likelihood. Albeit we find deviations from SE in some cases we conclude that these deviations are artefacts of the fit and that the assumptions of SE is physically meaningful.

Ex vivo UV-vis and FTIR photoacoustic spectroscopy of natural nanoemulsions from cellulose nanocrystals and saponins topically applied into the skin: Diffusion rates and physicochemical evaluation.

Nanoemulsions are increasingly gaining importance in the development of topically applied medicine and cosmetic products because their small droplets favor the penetration rates of active compounds into the body. In this scenario, the measurements of their diffusion rates as well as eventual physicochemical changes in the target tissues are of utmost importance. It is also recognized that the use of natural surfactants can avoid allergic reactions as frequently observed for synthetic products. The natural saponins extracted from Sapindus Saponaria have the property of forming foam and are exploited as biocompatible and biodegradable, while cellulose nanocrystals are known to increase the stability of a formulation avoiding the coalescence of drops at the interface. Therefore, nanoemulsions combining natural saponins and cellulose nanocrystals are promising systems that may facilitate greater diffusion rates of molecules into the skin, being candidates to substitute synthetic formulations. This study applied the Photoacoustic Spectroscopy technique to measure the diffusion rates and the physicochemical properties of nanoemulsified formulations containing saponins and cellulose nanocrystals topically applied to the skin. The ex vivo study combined the first-time photoacoustic measurements performed in both ultraviolet-visible and mid-infrared spectral regions. The toxicity of these formulations in L929 cells was also evaluated. The results showed that the formulations were able to propagate throughout the skin to a depth of approximately 756 µm, reaching the dermal side. The non-observation of absorbing band shifting or new bands in the FTIR spectra suggests that there were no structural changes in the skin as well as in the formulations after the nanoemulsions administration. The cytotoxicity results showed that the increase of cellulose nanocrystals concentration decreased cellular toxicity. In conclusion, the results demonstrated the advantage of combining photoacoustic methods in the ultraviolet-visible and mid-infrared spectral regions to analyze drug diffusion and interaction with the skin tissues. Both methods complement each other, allowing the confirmation of the nanoemulsion diffusion through the skin and also suggesting there were no detectable physicochemical changes in the tissues. Formulations stabilized with saponins and cellulose nanocrystals showed great potential for the development of topically administered cosmetics and drugs.

Photoacoustic for thermal diffusivity determination of fish scale: A methodology for environmental integrity monitoring.

In this work the thermal diffusivity (D) of Astyanax lacustris fish scale is investigated aiming to use it for environmental integrity certification. The D values were obtained by a relatively simple procedure by a photoacoustic method. The chosen fish species is from wide occurrence in Brasil's basins. It has short migration, and it has also been used as environmental bioindicator. The results obtained in 195 scales sampled from three different streams in the Midwest region in Brazil gives an average value of D ~ 4 × 10-3 cm2/s. ANCOVA analysis demonstrated that D values are able to differentiate among the three basins and indicates that it is dependent on the scales thickness and water conductivity. This last one is strongly affected by biotic and abiotic actions, so that D values measured by photoacoustic method can be used for interpreting the environmental integrity from where the fishes were sampled.

Target-Based Evaluation of "Drug-Like" Properties and Ligand Efficiencies.

Physicochemical descriptors commonly used to define "drug-likeness" and ligand efficiency measures are assessed for their ability to differentiate marketed drugs from compounds reported to bind to their efficacious target or targets. Using ChEMBL version 26, a data set of 643 drugs acting on 271 targets was assembled, comprising 1104 drug-target pairs having ≥100 published compounds per target. Taking into account changes in their physicochemical properties over time, drugs are analyzed according to their target class, therapy area, and route of administration. Recent drugs, approved in 2010-2020, display no overall differences in molecular weight, lipophilicity, hydrogen bonding, or polar surface area from their target comparator compounds. Drugs are differentiated from target comparators by higher potency, ligand efficiency (LE), lipophilic ligand efficiency (LLE), and lower carboaromaticity. Overall, 96% of drugs have LE or LLE values, or both, greater than the median values of their target comparator compounds.

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Drug Safety Data Curation and Modeling in ChEMBL: Boxed Warnings and Withdrawn Drugs.

The safety of marketed drugs is an ongoing concern, with some of the more frequently prescribed medicines resulting in serious or life-threatening adverse effects in some patients. Safety-related information for approved drugs has been curated to include the assignment of toxicity class(es) based on their withdrawn status and/or black box warning information described on medicinal product labels. The ChEMBL resource contains a wide range of bioactivity data types, from early "Discovery" stage preclinical data for individual compounds through to postclinical data on marketed drugs; the inclusion of the curated drug safety data set within this framework can support a wide range of safety-related drug discovery questions. The curated drug safety data set will be made freely available through ChEMBL and updated in future database releases.

The molecular structure and multifunctionality of the cryptic plant polymer suberin.

Suberin, a plant polyester, consists of polyfunctional long-chain fatty acids and glycerol and is an intriguing candidate as a novel antimicrobial material. We purified suberin from cork using ionic-liquid catalysis during which the glycerol bonds that ensure the polymeric nature of suberin remained intact or were only partially cleaved-yielding the closest to a native configuration reported to date. The chemistry of suberin, both in situ (in cryogenically ground cork) and ex situ (ionic-liquid extracted), was elucidated using high-resolution one- and two-dimensional solution-state NMR analyses. Centrifugation was used to isolate suberin particles of distinct densities and their monomeric composition, assembly, and bactericidal effect, inter alia, were assessed. Analysis of the molecular structure of suberin revealed the relative abundance of linear aliphatic vs. acylglycerol esters, comprising all acylglycerol configurations and the amounts of total carbonyls (C[bond, double bond]O), free acid end groups (COOH), OH aliphatics, and OH aromatics. Suberin centrifuged fractions revealed generic physiochemical properties and monomeric composition â€‹and self-assemble into polygonal structures that display distinct degrees of compactness when lyophilized. Suberin particles-suberinsomes-display bactericidal activity against major human pathogenic bacteria. Fingerprinting the multifunctionality of complex (plant) polyesters such as suberin allows for the identification of novel polymer assemblies with significant value-added properties.

Malnutrition in all its forms and socioeconomic status in Bolivia.

OBJECTIVE: To estimate the prevalence of malnutrition (undernutrition and excess BMI) among children under the age of 5 years and women of reproductive age in Bolivia considering three socioeconomic indicators: wealth, education and ethnicity. DESIGN: We used the 2008 nationally representative Bolivian Demographic and Health Survey (DHS). Malnutrition's prevalence was estimated by wealth, ethnicity and educational level. Wealth index was measured based on the DHS methodology and nutritional status by using WHO standards and indicators. Education level (EL) was categorized by years of formal education. SETTING: Bolivia. PARTICIPANTS: In total, 5·903 children <5 years, 3·345 adolescent women (15-19 years) and 12·297 women (20-49 years) with available information on anthropometric measurements·. RESULTS: A disproportionate prevalence of malnutrition was observed among different wealth groups: lower wealth tertiles show the higher prevalence of stunting (>30 %) and anaemia (>40 %) in all ages· The prevalence of overweight and obesity tends to rise with age from childhood (10·02-11·60) to adolescence (27·9-31·03), reaching highest levels in women of reproductive age (56·02-57·76). According to wealth tertiles, higher prevalence of overweight and obesity was found in children of high tertile (12·23), adolescent women of low (32·56) and adult women of medium tertile (63·08). CONCLUSIONS: The present study shows that currently Bolivia is in a transitional stage, faces not only the problem of undernutrition but also those of overnutrition, showing strong inequalities according to socioeconomic and education status. This study calls for state-specific policies keeping in view of the nature of inequality in malnutrition in the country and its differential characteristics across wealth status.

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.

Geant4-based electromagnetic background model for the CRESST dark matter experiment.

The CRESST (Cryogenic Rare Event Search with Superconducting Thermometers) dark matter search experiment aims for the detection of dark matter particles via elastic scattering off nuclei in CaWO 4 crystals. To understand the CRESST electromagnetic background due to the bulk contamination in the employed materials, a model based on Monte Carlo simulations was developed using the Geant4 simulation toolkit. The results of the simulation are applied to the TUM40 detector module of CRESST-II phase 2. We are able to explain up to ( 68 ± 16 ) % of the electromagnetic background in the energy range between 1 and 40 keV .

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.

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.

Physiological proteins in resource-limited herbivores experiencing a population die-off.

Nutrient availability is predicted to interact with herbivore population densities. Competition for low quality food at high density may reduce summer food intake, and in turn winter survival. Conversely, low population density may favor physiological recovery through better access to better quality spring forage. Here, we take advantage of the long-term study of the Soay sheep population of St. Kilda (Scotland) to measure plasma protein markers and immunity in two consecutive summers with contrasting population densities. We show that, following a winter die-off resulting in a shift to low population density, albumin and total proteins increased, but only in adult sheep. The effect was not solely attributable to selective disappearance of malnourished sheep. Similarly, the concentration of antibodies was higher following the die-off, potentially indicating recovery of immune function. Overall, our results are consistent with the physiological recovery of surviving individuals after a harsh winter.

Using ChEMBL web services for building applications and data processing workflows relevant to drug discovery.

INTRODUCTION: ChEMBL is a manually curated database of bioactivity data on small drug-like molecules, used by drug discovery scientists. Among many access methods, a REST API provides programmatic access, allowing the remote retrieval of ChEMBL data and its integration into other applications. This approach allows scientists to move from a world where they go to the ChEMBL web site to search for relevant data, to one where ChEMBL data can be simply integrated into their everyday tools and work environment. Areas covered: This review highlights some of the audiences who may benefit from using the ChEMBL API, and the goals they can address, through the description of several use cases. The examples cover a team communication tool (Slack), a data analytics platform (KNIME), batch job management software (Luigi) and Rich Internet Applications. Expert opinion: The advent of web technologies, cloud computing and micro services oriented architectures have made REST APIs an essential ingredient of modern software development models. The widespread availability of tools consuming RESTful resources have made them useful for many groups of users. The ChEMBL API is a valuable resource of drug discovery bioactivity data for professional chemists, chemistry students, data scientists, scientific and web developers.

Chemical Interaction Analysis of an Adhesive Containing 10-Methacryloyloxydecyl Dihydrogen Phosphate (10-MDP) With the Dentin in Noncarious Cervical Lesions.

The purpose of this study was to evaluate the chemical bonds of a self-etch 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) adhesive to natural noncarious cervical lesions (NCCLs) and compare them with those occurring in sclerotic dentin in artificially prepared defects (APDs). Four human teeth with natural NCCLs on the buccal surface were selected. Artificial defects matching the natural lesions were prepared on the lingual surface of the same teeth serving as control. Micro-Raman (MR) spectroscopy was used to quantify mineral content in natural NCCLs and in APDs. Fourier transform infrared-photoacoustic spectroscopy (FTIR-PAS) readouts were taken before and after adhesive application to analyze the protein matrix/mineral (M:M) ratio and chemical interactions between 10-MDP adhesive and dentin. The MR and FTIR-PAS spectra collected from natural NCCLs demonstrated a larger area of the band (961 cm-1, PO4) and lower M:M ratio, respectively, characterizing a hypermineralized dentin, compared with APDs. FTIR-PAS demonstrated emergence of a peak (1179 cm-1, P=O) in spectra after adhesive treatment, demonstrating a more intense chemical interaction in natural NCCLs. The results demonstrated that chemical bonding of 10-MDP adhesive to natural NCCLs is more intense, due to the hypermineralized surface, and suggest that it is unnecessary to remove the hypermineralized layer with burs, as this may decrease the chemical bonding potential of 10-MDP.

Potential role for ET-2 acting through ETA receptors in experimental colitis in mice.

OBJECTIVE AND DESIGN: This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. RESULTS: Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1ß, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ETA and ETB receptors mRNA were increased at 24, 48 and 72 h after colitis induction. CONCLUSIONS: Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ETA receptors might be a potential target for inflammatory bowel diseases.