EMBL's European Bioinformatics Institute (EMBL-EBI) in 2023.

The European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) is one of the world's leading sources of public biomolecular data. Based at the Wellcome Genome Campus in Hinxton, UK, EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe's only intergovernmental life sciences organisation. This overview summarises the latest developments in the services provided by EMBL-EBI data resources to scientific communities globally. These developments aim to ensure EMBL-EBI resources meet the current and future needs of these scientific communities, accelerating the impact of open biological data for all.

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.

EMBL's European Bioinformatics Institute (EMBL-EBI) in 2022.

The European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) is one of the world's leading sources of public biomolecular data. Based at the Wellcome Genome Campus in Hinxton, UK, EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe's only intergovernmental life sciences organisation. This overview summarises the status of services that EMBL-EBI data resources provide to scientific communities globally. The scale, openness, rich metadata and extensive curation of EMBL-EBI added-value databases makes them particularly well-suited as training sets for deep learning, machine learning and artificial intelligence applications, a selection of which are described here. The data resources at EMBL-EBI can catalyse such developments because they offer sustainable, high-quality data, collected in some cases over decades and made openly availability to any researcher, globally. Our aim is for EMBL-EBI data resources to keep providing the foundations for tools and research insights that transform fields across the life sciences.

Challenges and perspectives for naming lipids in the context of lipidomics.

INTRODUCTION: Lipids are key compounds in the study of metabolism and are increasingly studied in biology projects. It is a very broad family that encompasses many compounds, and the name of the same compound may vary depending on the community where they are studied. OBJECTIVES: In addition, their structures are varied and complex, which complicates their analysis. Indeed, the structural resolution does not always allow a complete level of annotation so the actual compound analysed will vary from study to study and should be clearly stated. For all these reasons the identification and naming of lipids is complicated and very variable from one study to another, it needs to be harmonized. METHODS & RESULTS: In this position paper we will present and discuss the different way to name lipids (with chemoinformatic and semantic identifiers) and their importance to share lipidomic results. CONCLUSION: Homogenising this identification and adopting the same rules is essential to be able to share data within the community and to map data on functional networks.

Accessing Rare α-Heterocyclic Aziridines via Brønsted Acid-catalyzed Michael Addition/Annulation: Scope, Limitations, and Mechanism.

We report an approach to the diastereoselective synthesis of 1,2-disubstituted heterocyclic aziridines. A Brønsted acid-catalyzed conjugate addition of anilines to trisubstituted heterocyclic chloroalkenes provides an intermediate 1,2-chloroamine. Diastereocontrol was found to vary significantly with solvent selection, with computational modelling confirming selective, spontaneous fragmentation in the presence of trace acids, proceeding through a pseudo-cyclic, protonated intermediate and transition state. These chloroamines can then be converted to the aziridine by treatment with LiHMDS with high stereochemical fidelity. This solvent-induced stereochemical enrichment thereby enables an efficient route to rare cis-aziridines with high dr. The scope, limitations, and mechanistic origins of selectivity are also presented.

In Situ Studies of Arylboronic Acids/Esters and R3SiCF3 Reagents: Kinetics, Speciation, and Dysfunction at the Carbanion-Ate Interface.

Reagent instability reduces the efficiency of chemical processes, and while much effort is devoted to reaction optimization, less attention is paid to the mechanistic causes of reagent decomposition. Indeed, the response is often to simply use an excess of the reagent. Two reaction classes with ubiquitous examples of this are the Suzuki-Miyaura cross-coupling of boronic acids/esters and the transfer of CF3 or CF2 from the Ruppert-Prakash reagent, TMSCF3. This Account describes some of the overarching features of our mechanistic investigations into their decomposition. In the first section we summarize how specific examples of (hetero)arylboronic acids can decompose via aqueous protodeboronation processes: Ar-B(OH)2 + H2O → ArH + B(OH)3. Key to the analysis was the development of a kinetic model in which pH controls boron speciation and heterocycle protonation states. This method revealed six different protodeboronation pathways, including self-catalysis when the pH is close to the pKa of the boronic acid, and protodeboronation via a transient aryl anionoid pathway for highly electron-deficient arenes. The degree of "protection" of boronic acids by diol-esterification is shown to be very dependent on the diol identity, with six-membered ring esters resulting in faster protodeboronation than the parent boronic acid. In the second section of the Account we describe 19F NMR spectroscopic analysis of the kinetics of the reaction of TMSCF3 with ketones, fluoroarenes, and alkenes. Processes initiated by substoichiometric "TBAT" ([Ph3SiF2][Bu4N]) involve anionic chain reactions in which low concentrations of [CF3]- are rapidly and reversibly liberated from a siliconate reservoir, [TMS(CF3)2][Bu4N]. Increased TMSCF3 concentrations reduce the [CF3]- concentration and thus inhibit the rates of CF3 transfer. Computation and kinetics reveal that the TMSCF3 intermolecularly abstracts fluoride from [CF3]- to generate the CF2, in what would otherwise be an endergonic α-fluoride elimination. Starting from [CF3]- and CF2, a cascade involving perfluoroalkene homologation results in the generation of a hindered perfluorocarbanion, [C11F23]-, and inhibition. The generation of CF2 from TMSCF3 is much more efficiently mediated by NaI, and in contrast to TBAT, the process undergoes autoacceleration. The process involves NaI-mediated α-fluoride elimination from [CF3][Na] to generate CF2 and a [NaI·NaF] chain carrier. Chain-branching, by [(CF2)3I][Na] generated in situ (CF2 + TFE + NaI), causes autoacceleration. Alkenes that efficiently capture CF2 attenuate the chain-branching, suppress autoacceleration, and lead to less rapid difluorocyclopropanation. The Account also highlights how a collaborative approach to experiment and computation enables mechanistic insight for control of processes.

Asymmetric Synthesis of Heterocyclic Chloroamines and Aziridines by Enantioselective Protonation of Catalytically Generated Enamines.

We report a method for the synthesis of chiral vicinal chloroamines via asymmetric protonation of catalytically generated prochiral chloroenamines using chiral Brønsted acids. The process is highly enantioselective, with the origin of asymmetry and catalyst substituent effects elucidated by DFT calculations. We show the utility of the method as an approach to the synthesis of a broad range of heterocycle-substituted aziridines by treatment of the chloroamines with base in a one-pot process, as well as the utility of the process to allow access to vicinal diamines.

A Lewis Base Nucleofugality Parameter, NFB, and Its Application in an Analysis of MIDA-Boronate Hydrolysis Kinetics.

The kinetics of quinuclidine displacement of BH3 from a wide range of Lewis base borane adducts have been measured. Parameterization of these rates has enabled the development of a nucleofugality scale (NFB), shown to quantify and predict the leaving group ability of a range of other Lewis bases. Additivity observed across a number of series R'3-nRnX (X = P, N; R' = aryl, alkyl) has allowed the formulation of related substituent parameters (nfPB, nfAB), providing a means of calculating NFB values for a range of Lewis bases that extends far beyond those experimentally derived. The utility of the nucleofugality parameter is explored by the correlation of the substituent parameter nfPB with the hydrolyses rates of a series of alkyl and aryl MIDA boronates under neutral conditions. This has allowed the identification of MIDA boronates with heteroatoms proximal to the reacting center, showing unusual kinetic lability or stability to hydrolysis.

Heavy-Atom Kinetic Isotope Effects: Primary Interest or Zero Point?

Chemists have many options for elucidating reaction mechanisms. Global kinetic analysis and classic transition-state probes (e.g., LFERs, Eyring) inevitably form the cornerstone of any strategy, yet their application to increasingly sophisticated synthetic methodologies often leads to a wide range of indistinguishable mechanistic proposals. Computational chemistry provides powerful tools for narrowing the field in such cases, yet wholly simulated mechanisms must be interpreted with great caution. Heavy-atom kinetic isotope effects (KIEs) offer an exquisite but underutilized method for reconciling the two approaches, anchoring the theoretician in the world of calculable observables and providing the experimentalist with atomistic insights. This Perspective provides a personal outlook on this synergy. It surveys the computation of heavy-atom KIEs and their measurement by NMR spectroscopy, discusses recent case studies, highlights the intellectual reward that lies in alignment of experiment and theory, and reflects on the changes required in chemical education in the area.

Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pKa of the boronic acid/ester.

Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.

Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs with genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate cellular drug mechanism-of-action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein-protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin-protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development.

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.

Mapping Ligand-Shape Space for Protein-Ligand Systems: Distinguishing Key-in-Lock and Hand-in-Glove Proteins.

Many of the recently developed methods to study the shape of molecules permit one conformation of one molecule to be compared to another conformation of the same or a different molecule: a relative shape. Other methods provide an absolute description of the shape of a conformation that does not rely on comparisons or overlays. Any absolute description of shape can be used to generate a self-organizing map (shape map) that places all molecular shapes relative to one another; in the studies reported here, the shape fingerprint and ultrafast shape recognition methods are employed to create such maps. In the shape maps, molecules that are near one another have similar shapes, and the maps for the 102 targets in the DUD-E set have been generated. By examining the distribution of actives in comparison with their physical-property-matched decoys, we show that the proteins of key-in-lock type (relatively rigid receptor and ligand) can be distinguished from those that are more of a hand-in-glove type (more flexible receptor and ligand). These are linked to known differences in protein flexibility and binding-site size.

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.

Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions.

The mechanism of CF2 transfer from TMSCF3 (1), mediated by TBAT (2-12 mol %) or by NaI (5-20 mol %), has been investigated by in situ/stopped-flow 19F NMR spectroscopic analysis of the kinetics of alkene difluorocyclopropanation and competing TFE/c-C3F6/homologous perfluoroanion generation, 13C/2H KIEs, LFERs, CF2 transfer efficiency and selectivity, the effect of inhibitors, and density functional theory (DFT) calculations. The reactions evolve with profoundly different kinetics, undergoing autoinhibition (TBAT) or quasi-stochastic autoacceleration (NaI) and cogenerating perfluoroalkene side products. An overarching mechanism involving direct and indirect fluoride transfer from a CF3 anionoid to TMSCF3 (1) has been elucidated. It allows rationalization of why the NaI-mediated process is more effective for less-reactive alkenes and alkynes, why a large excess of TMSCF3 (1) is required in all cases, and why slow-addition protocols can be of benefit. Issues relating to exothermicity, toxicity, and scale-up are also noted.

Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study.

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C-F stereocentre in high enantioselectivity, and is also amenable to stereogenic C-CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.

Racemisation in Chemistry and Biology.

The two enantiomers of a compound often have profoundly different biological properties and thus their liability to racemisation in aqueous solutions is an important piece of information. The authors reviewed the available data concerning the process of racemisation in vivo, in the presence of biological molecules (e.g., racemase enzymes, serum albumin, cofactors and derivatives) and under purely chemical but aqueous conditions (acid, base and other aqueous systems). Mechanistic studies are described critically in light of reported kinetic data. The types of experimental measurement that can be used to effectively determine rate constants of racemisation in various conditions are discussed and the data they provide is summarised. The proposed origins of enzymatic racemisation are presented and suggest ways to promote the process that are different from processes taking place in bulk water. Experimental and computational studies that provide understanding and quantitative predictions of racemisation risk are also presented.

Hotspots API: A Python Package for the Detection of Small Molecule Binding Hotspots and Application to Structure-Based Drug Design.

Methods that survey protein surfaces for binding hotspots can help to evaluate target tractability and guide exploration of potential ligand binding regions. Fragment Hotspot Maps builds upon interaction data mined from the CSD (Cambridge Structural Database) and exploits the idea of identifying hotspots using small chemical fragments, which is now widely used to design new drug leads. Prior to this publication, Fragment Hotspot Maps was only publicly available through a web application. To increase the accessibility of this algorithm we present the Hotspots API (application programming interface), a toolkit that offers programmatic access to the core Fragment Hotspot Maps algorithm, thereby facilitating the interpretation and application of the analysis. To demonstrate the package's utility, we present a workflow which automatically derives protein hydrogen-bond constraints for molecular docking with GOLD. The Hotspots API is available from https://github.com/prcurran/hotspots under the MIT license and is dependent upon the commercial CSD Python API.

Impact of Pit-Crew Cardiopulmonary Resuscitation on Out-of-Hospital Cardiac Arrest in Saskatoon.

BACKGROUND: In the prehospital setting, pit-crew models of cardiopulmonary resuscitation (CPR) have shown improvements in survival after out-of-hospital cardiac arrest (OHCA). Certain districts in North America have adopted this model, including Saskatoon, Saskatchewan, Canada. OBJECTIVES: Our objectives were to determine whether pit-crew CPR has an impact on survival to discharge after OHCA in Saskatoon, Canada. METHODS: This was a retrospective pre- and postintervention study. All adult patients who had an OHCA between January 1, 2011 and December 31, 2017 of presumed cardiac origin, in which the resuscitation attempt included CPR by trained prehospital responders, were considered for analysis. Our primary outcome was survival to discharge. Survival to admission and return of spontaneous circulation were secondary outcomes. RESULTS: There were 860 OHCAs considered for our study. After 46 exclusions there were 442 in the non-pit-crew group (average age 63.7 years; 64.5% male) and 372 in the pit-crew group (average age 63.5 years; 67.5% male). Survival to discharge after an OHCA was 10.4% (95% confidence interval 7.7-13.6%) in the non-pit-crew group and 12.4% (95% CI 9.2-16.2%) in the pit-crew group, which did not meet statistical significance. Return of spontaneous circulation and survival to admission were 48.4% and 31.3%, respectively, in the non-pit-crew group and 46.7% and 32.3%, respectively, in the pit-crew group. CONCLUSIONS: In our study, implementation of a pit-crew CPR model was not associated with an improvement in survival to discharge after OHCA.

Canadian Electricity Markets during the COVID-19 Pandemic: An Initial Assessment.

This article examines the effect of the coronavirus disease 2019 (COVID-19) pandemic on electricity markets across select Canadian provinces, using available data. Using high-frequency electricity data, we find electricity demand declined by roughly 10 percent in Ontario and by about 5 percent in Alberta, British Columbia, and New Brunswick. On the supply side, in Alberta we find reductions from some natural gas plants and an increase in net generation from the oil sands region, whereas Ontario sees an increase in net electricity exports. Policy implications include potential rate impacts as a result of fixed charges spread over a smaller rate base, the potential use of electricity data as a real-time economic indicator during the pandemic, and a call to arms to make electricity data across all Canadian provinces more readily available.

Les auteurs examinent l'effet de la pandémie de COVID-19 sur les marchés de l'électricité dans certaines provinces canadiennes en s'appuyant sur les données disponibles. Leur analyse des données relatives à l'électricité à haute fréquence révèle que la demande d'électricité a diminué d'environ 10 % en Ontario, moins dans les autres provinces étudiées. Du côté de l'offre, en Alberta, ils observent que la production de certaines centrales au gaz naturel a diminué, mais que la production nette à partir des installations des sables bitumineux a augmenté, tandis que l'Ontario a enregistré une augmentation des exportations nettes. Les répercussions de ces constats sur les politiques sont notamment leur incidence potentielle sur les tarifs en raison de frais fixes répartis sur une base tarifaire plus restreinte, l'utilisation potentielle des données sur l'électricité comme indicateur économique en temps réel pendant la pandémie et un cri du cœur pour que soit facilité l'accès aux données sur l'électricité dans toutes les provinces canadiennes.