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1.
Nucleic Acids Res ; 48(D1): D431-D439, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31701147

RESUMO

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program with the goal of generating a large-scale and comprehensive catalogue of perturbation-response signatures by utilizing a diverse collection of perturbations across many model systems and assay types. The LINCS Data Portal (LDP) has been the primary access point for the compendium of LINCS data and has been widely utilized. Here, we report the first major update of LDP (http://lincsportal.ccs.miami.edu/signatures) with substantial changes in the data architecture and APIs, a completely redesigned user interface, and enhanced curated metadata annotations to support more advanced, intuitive and deeper querying, exploration and analysis capabilities. The cornerstone of this update has been the decision to reprocess all high-level LINCS datasets and make them accessible at the data point level enabling users to directly access and download any subset of signatures across the entire library independent from the originating source, project or assay. Access to the individual signatures also enables the newly implemented signature search functionality, which utilizes the iLINCS platform to identify conditions that mimic or reverse gene set queries. A newly designed query interface enables global metadata search with autosuggest across all annotations associated with perturbations, model systems, and signatures.


Assuntos
Biologia Celular , Bases de Dados Factuais , Ensaios Clínicos como Assunto , Biologia Computacional , Curadoria de Dados , Humanos , Armazenamento e Recuperação da Informação , Metadados , National Institutes of Health (U.S.) , Estados Unidos , Interface Usuário-Computador
2.
Nucleic Acids Res ; 46(D1): D558-D566, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29140462

RESUMO

The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content.


Assuntos
Bases de Dados Factuais , Biologia Celular , Biologia Computacional , Curadoria de Dados , Bases de Dados Genéticas , Epigenômica , Humanos , Metadados , Proteômica , Software , Biologia de Sistemas , Interface Usuário-Computador
3.
BMC Bioinformatics ; 18(Suppl 17): 556, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29322930

RESUMO

BACKGROUND: Aiming to understand cellular responses to different perturbations, the NIH Common Fund Library of Integrated Network-based Cellular Signatures (LINCS) program involves many institutes and laboratories working on over a thousand cell lines. The community-based Cell Line Ontology (CLO) is selected as the default ontology for LINCS cell line representation and integration. RESULTS: CLO has consistently represented all 1097 LINCS cell lines and included information extracted from the LINCS Data Portal and ChEMBL. Using MCF 10A cell line cells as an example, we demonstrated how to ontologically model LINCS cellular signatures such as their non-tumorigenic epithelial cell type, three-dimensional growth, latrunculin-A-induced actin depolymerization and apoptosis, and cell line transfection. A CLO subset view of LINCS cell lines, named LINCS-CLOview, was generated to support systematic LINCS cell line analysis and queries. In summary, LINCS cell lines are currently associated with 43 cell types, 131 tissues and organs, and 121 cancer types. The LINCS-CLO view information can be queried using SPARQL scripts. CONCLUSIONS: CLO was used to support ontological representation, integration, and analysis of over a thousand LINCS cell line cells and their cellular responses.


Assuntos
Mama/metabolismo , Biologia Computacional/métodos , Regulação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Neoplasias/genética , Apoptose/efeitos dos fármacos , Mama/citologia , Mama/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Humanos , Macrolídeos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tiazolidinas/farmacologia
4.
J Comput Aided Mol Des ; 25(9): 873-83, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21904909

RESUMO

The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 22/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Domínio Catalítico , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 22/química
5.
Bioorg Med Chem Lett ; 19(8): 2354-9, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19303288

RESUMO

Soluble epoxide hydrolase (sEH) is a novel target for the treatment of hypertension and vascular inflammation. A new class of potent non-urea sEH inhibitors was identified via high throughput screening (HTS) and chemical modification. IC(50)s of the most potent compounds range from micromolar to low nanomolar.


Assuntos
Descoberta de Drogas/métodos , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Ureia/metabolismo , Humanos , Solubilidade , Relação Estrutura-Atividade , Ureia/química , Ureia/classificação , Ureia/farmacologia
8.
J Biomol Screen ; 13(1): 17-28, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18227223

RESUMO

Kinases are important drug discovery targets for a wide variety of therapeutic indications; consequently, the measurement of kinase activity remains a common high-throughput screening (HTS) application. Recently, enzyme-coupled luciferase-kinase (LK) format assays have been introduced. This format measures luminescence resulting from metabolism of adenosine triphosphate (ATP) via a luciferin/luciferase-coupled reaction. In the research presented here, 1536-well format time-resolved fluorescence resonance energy transfer (TR-FRET) and LK assays were created to identify novel Rho-associated kinase II (ROCK-II) inhibitors. HTS campaigns for both assays were conducted in this miniaturized format. It was found that both assays were able to consistently reproduce the expected pharmacology of inhibitors known to be specific to ROCK-II (fasudil IC50: 283 +/- 27 nM and 336 +/- 54 nM for TR-FRET and LK assays, respectively; Y-27632 IC50: 133 +/- 7.8 nM and 150 +/- 22 nM for TR-FRET and LK assays, respectively). In addition, both assays proved robust for HTS efforts, demonstrating excellent plate Z' values during the HTS campaign (0.84 +/- 0.03; 0.72 +/- 0.05 for LK and TR-FRET campaigns, respectively). Both formats identified scaffolds of known and novel ROCK-II inhibitors with similar sensitivity. A comparison of the performance of these 2 assay formats in an HTS campaign was enabled by the existence of a subset of 25,000 compounds found in both our institutional and the Molecular Library Screening Center Network screening files. Analysis of the HTS campaign results based on this subset of common compounds showed that both formats had comparable total hit rates, hit distributions, amount of hit clusters, and format-specific artifact. It can be concluded that both assay formats are suitable for the discovery of ROCK-II inhibitors, and the choice of assay format depends on reagents and/or screening technology available.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Transferência Ressonante de Energia de Fluorescência/métodos , Medições Luminescentes/métodos , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Sequência de Bases , Primers do DNA/genética , Humanos , Técnicas In Vitro , Luciferases , Miniaturização , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Quinases Associadas a rho/genética
9.
Bioorg Med Chem Lett ; 18(9): 2840-4, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18434147

RESUMO

We report here a class of thiazolidine-2,4-diones and 2-thioxothiazolidin-4-ones as potent inhibitors of the lymphoid specific tyrosine phosphatase (Lyp) identified from high throughput screens. Chemical modification by incorporating the known phosphotyrosine (pTyr) mimics led to the discovery of a salicylate-based inhibitor with submicromolar potency.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 22/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Tiazolidinas/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Modelos Químicos , Mimetismo Molecular , Fosfotirosina/química , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinas/síntese química
10.
Bioorg Med Chem Lett ; 18(1): 329-35, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18024113

RESUMO

We describe here a series of N-(quinolin-8-yl)benzenesulfonamides capable of suppressing the NFkappaB pathway identified from two high-throughput screens run at two centers of the NIH Molecular Libraries Initiative. These small molecules were confirmed in both primary and secondary assays of NFkappaB activation and expanded upon through analogue synthesis. The series exhibited potencies in the cell-based assays at as low as 0.6 microM, and several indications suggest that the targeted activity lies within a common region of the NFkappaB pathway.


Assuntos
NF-kappa B/antagonistas & inibidores , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Técnicas de Química Combinatória , Regulação para Baixo/efeitos dos fármacos , NF-kappa B/metabolismo , Quinolinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Benzenossulfonamidas
11.
Sci Data ; 5: 180117, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29917015

RESUMO

The NIH-funded LINCS Consortium is creating an extensive reference library of cell-based perturbation response signatures and sophisticated informatics tools incorporating a large number of perturbagens, model systems, and assays. To date, more than 350 datasets have been generated including transcriptomics, proteomics, epigenomics, cell phenotype and competitive binding profiling assays. The large volume and variety of data necessitate rigorous data standards and effective data management including modular data processing pipelines and end-user interfaces to facilitate accurate and reliable data exchange, curation, validation, standardization, aggregation, integration, and end user access. Deep metadata annotations and the use of qualified data standards enable integration with many external resources. Here we describe the end-to-end data processing and management at the DCIC to generate a high-quality and persistent product. Our data management and stewardship solutions enable a functioning Consortium and make LINCS a valuable scientific resource that aligns with big data initiatives such as the BD2K NIH Program and concords with emerging data science best practices including the findable, accessible, interoperable, and reusable (FAIR) principles.


Assuntos
Curadoria de Dados , Metadados , Animais , Conjuntos de Dados como Assunto , Humanos , Armazenamento e Recuperação da Informação , National Institutes of Health (U.S.) , Estados Unidos
12.
Cell Syst ; 6(1): 13-24, 2018 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-29199020

RESUMO

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.


Assuntos
Catalogação/métodos , Biologia de Sistemas/métodos , Biologia Computacional/métodos , Bases de Dados de Compostos Químicos/normas , Perfilação da Expressão Gênica/métodos , Biblioteca Gênica , Humanos , Armazenamento e Recuperação da Informação/métodos , Programas Nacionais de Saúde , National Institutes of Health (U.S.)/normas , Transcriptoma , Estados Unidos
13.
J Biomed Semantics ; 8(1): 50, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29122012

RESUMO

BACKGROUND: One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. RESULTS: As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. CONCLUSIONS: DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource.


Assuntos
Ontologias Biológicas , Biologia Computacional/métodos , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Proteínas/classificação , Proteínas/genética , Proteínas/metabolismo , Semântica , Software
14.
J Biomed Semantics ; 5(Suppl 1 Proceedings of the Bio-Ontologies Spec Interest G): S5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25093074

RESUMO

The lack of established standards to describe and annotate biological assays and screening outcomes in the domain of drug and chemical probe discovery is a severe limitation to utilize public and proprietary drug screening data to their maximum potential. We have created the BioAssay Ontology (BAO) project (http://bioassayontology.org) to develop common reference metadata terms and definitions required for describing relevant information of low-and high-throughput drug and probe screening assays and results. The main objectives of BAO are to enable effective integration, aggregation, retrieval, and analyses of drug screening data. Since we first released BAO on the BioPortal in 2010 we have considerably expanded and enhanced BAO and we have applied the ontology in several internal and external collaborative projects, for example the BioAssay Research Database (BARD). We describe the evolution of BAO with a design that enables modeling complex assays including profile and panel assays such as those in the Library of Integrated Network-based Cellular Signatures (LINCS). One of the critical questions in evolving BAO is the following: how can we provide a way to efficiently reuse and share among various research projects specific parts of our ontologies without violating the integrity of the ontology and without creating redundancies. This paper provides a comprehensive answer to this question with a description of a methodology for ontology modularization using a layered architecture. Our modularization approach defines several distinct BAO components and separates internal from external modules and domain-level from structural components. This approach facilitates the generation/extraction of derived ontologies (or perspectives) that can suit particular use cases or software applications. We describe the evolution of BAO related to its formal structures, engineering approaches, and content to enable modeling of complex assays and integration with other ontologies and datasets.

15.
J Biomol Screen ; 19(5): 803-16, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24518066

RESUMO

The National Institutes of Health Library of Integrated Network-based Cellular Signatures (LINCS) program is generating extensive multidimensional data sets, including biochemical, genome-wide transcriptional, and phenotypic cellular response signatures to a variety of small-molecule and genetic perturbations with the goal of creating a sustainable, widely applicable, and readily accessible systems biology knowledge resource. Integration and analysis of diverse LINCS data sets depend on the availability of sufficient metadata to describe the assays and screening results and on their syntactic, structural, and semantic consistency. Here we report metadata specifications for the most important molecular and cellular components and recommend them for adoption beyond the LINCS project. We focus on the minimum required information to model LINCS assays and results based on a number of use cases, and we recommend controlled terminologies and ontologies to annotate assays with syntactic consistency and semantic integrity. We also report specifications for a simple annotation format (SAF) to describe assays and screening results based on our metadata specifications with explicit controlled vocabularies. SAF specifically serves to programmatically access and exchange LINCS data as a prerequisite for a distributed information management infrastructure. We applied the metadata specifications to annotate large numbers of LINCS cell lines, proteins, and small molecules. The resources generated and presented here are freely available.


Assuntos
Biologia Computacional/métodos , Ensaios de Triagem em Larga Escala/métodos , Anticorpos/química , Linhagem Celular , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Biblioteca Gênica , Humanos , Internet , Cinética , Masculino , Metadados , Mutação , National Institutes of Health (U.S.) , Neoplasias Ovarianas/metabolismo , Proteínas/química , RNA Interferente Pequeno/metabolismo , Bibliotecas de Moléculas Pequenas/química , Estados Unidos
16.
PLoS One ; 7(11): e49198, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23155465

RESUMO

Huge amounts of high-throughput screening (HTS) data for probe and drug development projects are being generated in the pharmaceutical industry and more recently in the public sector. The resulting experimental datasets are increasingly being disseminated via publically accessible repositories. However, existing repositories lack sufficient metadata to describe the experiments and are often difficult to navigate by non-experts. The lack of standardized descriptions and semantics of biological assays and screening results hinder targeted data retrieval, integration, aggregation, and analyses across different HTS datasets, for example to infer mechanisms of action of small molecule perturbagens. To address these limitations, we created the BioAssay Ontology (BAO). BAO has been developed with a focus on data integration and analysis enabling the classification of assays and screening results by concepts that relate to format, assay design, technology, target, and endpoint. Previously, we reported on the higher-level design of BAO and on the semantic querying capabilities offered by the ontology-indexed triple store of HTS data. Here, we report on our detailed design, annotation pipeline, substantially enlarged annotation knowledgebase, and analysis results. We used BAO to annotate assays from the largest public HTS data repository, PubChem, and demonstrate its utility to categorize and analyze diverse HTS results from numerous experiments. BAO is publically available from the NCBO BioPortal at http://bioportal.bioontology.org/ontologies/1533. BAO provides controlled terminology and uniform scope to report probe and drug discovery screening assays and results. BAO leverages description logic to formalize the domain knowledge and facilitate the semantic integration with diverse other resources. As a consequence, BAO offers the potential to infer new knowledge from a corpus of assay results, for example molecular mechanisms of action of perturbagens.


Assuntos
Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Bases de Dados Factuais
17.
J Med Chem ; 54(2): 562-71, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21190368

RESUMO

The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC(50) values between 0.27 and 6.2 µM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.


Assuntos
Benzofuranos/síntese química , Proteína Tirosina Fosfatase não Receptora Tipo 22/antagonistas & inibidores , Salicilatos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Humanos , Células Jurkat , Modelos Moleculares , Fatores de Transcrição NFATC/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 22/química , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores de Antígenos de Linfócitos T/fisiologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Salicilatos/química , Salicilatos/farmacologia , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fator de Transcrição AP-1/metabolismo
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