ABSTRACT
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.
Subject(s)
Academies and Institutes , Computational Biology , Computational Biology/organization & administration , Computational Biology/trends , Academies and Institutes/organization & administration , Academies and Institutes/trends , Databases, Nucleic Acid , EuropeABSTRACT
The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.
ABSTRACT
The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target-disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.
Subject(s)
Antineoplastic Agents/therapeutic use , Drugs, Investigational/therapeutic use , Knowledge Bases , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Software , Antineoplastic Agents/chemistry , Databases, Factual , Datasets as Topic , Drug Discovery/methods , Drugs, Investigational/chemistry , Humans , Internet , Neoplasms/classification , Neoplasms/genetics , Neoplasms/pathologyABSTRACT
Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.
Subject(s)
Databases, Genetic , Genome, Human , Inflammatory Bowel Diseases/genetics , Molecular Targeted Therapy/methods , Quantitative Trait Loci , Software , Chromatin/chemistry , Chromatin/metabolism , Datasets as Topic , Drug Discovery/methods , Drug Repositioning/methods , Genome-Wide Association Study , Genotype , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Internet , Phenotype , Quantitative Trait, HeritableABSTRACT
The Open Targets Platform integrates evidence from genetics, genomics, transcriptomics, drugs, animal models and scientific literature to score and rank target-disease associations for drug target identification. The associations are displayed in an intuitive user interface (https://www.targetvalidation.org), and are available through a REST-API (https://api.opentargets.io/v3/platform/docs/swagger-ui) and a bulk download (https://www.targetvalidation.org/downloads/data). In addition to target-disease associations, we also aggregate and display data at the target and disease levels to aid target prioritisation. Since our first publication two years ago, we have made eight releases, added new data sources for target-disease associations, started including causal genetic variants from non genome-wide targeted arrays, added new target and disease annotations, launched new visualisations and improved existing ones and released a new web tool for batch search of up to 200 targets. We have a new URL for the Open Targets Platform REST-API, new REST endpoints and also removed the need for authorisation for API fair use. Here, we present the latest developments of the Open Targets Platform, expanding the evidence and target-disease associations with new and improved data sources, refining data quality, enhancing website usability, and increasing our user base with our training workshops, user support, social media and bioinformatics forum engagement.
Subject(s)
Computational Biology/methods , Databases, Genetic , Genomics/methods , Information Storage and Retrieval/methods , Molecular Targeted Therapy/methods , Computational Biology/trends , Gene Expression Profiling/methods , Genomics/trends , Humans , Information Storage and Retrieval/trends , Internet , Reproducibility of Results , SoftwareABSTRACT
The Suzuki-Miyaura (SM) reaction is one of the most important methods for C-C bond formation in chemical synthesis. In this communication, we show for the first time that the low toxicity, inexpensive element zinc is able to catalyze SM reactions. The cross-coupling of benzyl bromides with aryl borates is catalyzed by ZnBr2 , in a process that is free from added ligand, and is compatible with a range of functionalized benzyl bromides and arylboronic acid pinacol esters. Initial mechanistic investigations indicate that the selective in situ formation of triaryl zincates is crucial to promote selective cross-coupling reactivity, which is facilitated by employing an arylborate of optimal nucleophilicity.
ABSTRACT
The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.
Subject(s)
Data Science , Drug Discovery , Machine Learning , Drug Discovery/methods , Data Science/methods , Humans , Artificial Intelligence , Information Dissemination/methods , Data Mining/methods , Cloud Computing , Databases, FactualABSTRACT
Tetramethylethylenediamine (TMEDA) acts as cheap and readily removed ligand in the iron-catalyzed coupling of alkyl Grignard reagents and activated aryl chlorides. The use of TMEDA allows for low ligand and iron catalyst loading as well as an increased reaction concentration and an ambient reaction temperature on a mole scale.
Subject(s)
Ethylenediamines/chemistry , Hydrocarbons, Chlorinated/chemistry , Iron/chemistry , Organometallic Compounds/chemistry , Temperature , Amides/chemical synthesis , Amides/chemistry , Catalysis , Esters/chemical synthesis , Esters/chemistry , Ligands , Molecular StructureABSTRACT
The Hiyama cross-coupling reaction is a powerful method for carbon-carbon bond formation. To date, the substrate scope of this reaction has predominantly been limited to sp(2)-sp(2) coupling reactions. Herein, the palladium-catalysed Hiyama type cross-coupling of vinyldisiloxanes with benzylic and allylic bromides, chlorides, tosylates and mesylates is reported. A wide variety of functional groups were tolerated, and the synthetic utility of the methodology was exemplified through the efficient total synthesis of the cytotoxic natural product bussealin A. In addition, the antiproliferative ability of bussealin A was evaluated in two cancer-cell lines.
Subject(s)
Arylsulfonates/chemistry , Benzene Derivatives/chemistry , Hydrocarbons, Halogenated/chemistry , Siloxanes/chemistry , Vinyl Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Palladium/chemistryABSTRACT
The prevalence of the biaryl structural motif in biologically interesting and synthetically important molecules has inspired considerable interest in the development of methods for aryl-aryl bond formation. Herein we describe a novel strategy for this process involving the fluoride-free, palladium-catalysed cross-coupling of readily accessible aryldisiloxanes and aryl bromides. Using a statistical-based optimisation process, preparatively useful reaction conditions were formulated to allow the cross-coupling of a wide range of different substrates. This methodology represents an attractive, cost-efficient, flexible and robust alternative to the traditional transition-metal-catalysed routes typically used to generate molecules containing the privileged biaryl scaffold.
Subject(s)
Cross-Linking Reagents/chemistry , Fluorides/chemistry , Hydrocarbons, Brominated/chemistry , Palladium/chemistry , Siloxanes/chemistry , Catalysis , Molecular StructureABSTRACT
A general procedure for the palladium-catalyzed annulation of substituted haloanilines with norbornadiene gives functionalized indolines in 51-98% yield. These indolines can be rapidly converted to benzenoid-substituted indoles and tricyclic indolines. Extension to the use of substituted halobenzamides gives functionalized isoquinolinones in up to 86% yield.
Subject(s)
Acetylene/chemistry , Aniline Compounds/chemistry , Benzamides/chemistry , Indoles/chemical synthesis , Isoquinolines/chemical synthesis , Norbornanes/chemistry , Palladium/chemistry , Indoles/chemistry , Isoquinolines/chemistryABSTRACT
The use of manganese(III) acetate in combination with copper(II) triflate allows the synthesis of [3.3.0]-bicyclic gamma-lactones from 4-pentenylmalonates in excellent yields.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Lactones/chemical synthesis , Acetates/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Copper/chemistry , Cyclization , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Free Radicals/chemistry , Lactones/chemistry , Malonates/chemistry , Mesylates/chemistry , Molecular Structure , Organometallic Compounds/chemistry , Oxidation-ReductionABSTRACT
[reaction: see text] An annulation reaction proceeding by the intermolecular addition of an arylpalladium(II) halide across a strained alkene, followed by an intramolecular C-H functionalization of a pendant heterocycle is described. A variety of polycyclic heterocycles have been prepared from readily accessible haloaryl heterocycles by annulation with a range of strained alkene partners.
Subject(s)
Alkenes/chemistry , Macrocyclic Compounds/chemistry , Palladium/chemistry , Bromides/chemistry , Catalysis , Norbornanes/chemistry , Pyrroles/chemistrySubject(s)
Drug Approval , Human Genetics , Humans , United States , United States Food and Drug AdministrationABSTRACT
Exposure of cyclic alkenes bearing a carboxylic acid and a malonate group to manganese(III) acetate and an appropriate copper(II) salt provides the corresponding tricyclic gamma-lactones in good yield.
Subject(s)
4-Butyrolactone/analogs & derivatives , Heterocyclic Compounds, 3-Ring/chemical synthesis , Manganese/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Acetates/chemistry , Catalysis , Copper/chemistry , Cyclization , Heterocyclic Compounds, 3-Ring/chemistry , Models, Molecular , Molecular Conformation , X-Ray DiffractionABSTRACT
A six step transformation of prednisolone to 17α,21-dihydroxy-9ß,11ß-epoxy-16α-amethylpregna-1,4-diene-3,20-dione 21-acetate has been achieved in 13% unoptimised yield. Novel conditions for effecting a Mattox rearrangement and double dehydration of prednisolone were identified. Enhanced knowledge on the oxidation of silyl Δ(19,20)-enol ethers and structural factors that impact the success of the oxidation are also presented.
Subject(s)
Glucocorticoids/chemical synthesis , Prednisolone/analogs & derivatives , Prednisolone/chemistry , Oxidation-Reduction , Prednisolone/chemical synthesisABSTRACT
A norbornene-mediated palladium-catalyzed sequence is described in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one reaction vessel. The aryl-heteroaryl bond-forming step occurs via a direct arylation reaction. A number of six-, seven-, and eight-membered ring-annulated indoles, pyrroles, pyrazoles, and azaindoles were synthesized from the corresponding bromoalkyl azole and an aryl iodide.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Nitrogen/chemistry , Palladium/chemistry , Alkylation , Catalysis , Heterocyclic Compounds/chemistryABSTRACT
Unsaturated malonates bearing pendant alcohols yield carbocycles tethered to oxygen heterocycles on exposure to manganese(iii) acetate and an appropriate copper(ii) salt.