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1.
Proc Natl Acad Sci U S A ; 115(42): 10750-10755, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30282735

RESUMO

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.


Assuntos
Antiprotozoários/farmacologia , Criptosporidiose/tratamento farmacológico , Cryptosporidium/efeitos dos fármacos , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Criptosporidiose/parasitologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL
2.
Proc Natl Acad Sci U S A ; 105(26): 9059-64, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18579783

RESUMO

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.


Assuntos
Antimaláricos/análise , Antimaláricos/farmacologia , Biologia Computacional , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Análise por Conglomerados , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos/efeitos dos fármacos , Antagonistas do Ácido Fólico/análise , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Malária/tratamento farmacológico , Modelos Moleculares , Parasitos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Reprodutibilidade dos Testes , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/química
3.
Genetics ; 176(1): 675-83, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17409088

RESUMO

The discovery of quantitative trait loci (QTL) in model organisms has relied heavily on the ability to perform controlled breeding to generate genotypic and phenotypic diversity. Recently, we and others have demonstrated the use of an existing set of diverse inbred mice (referred to here as the mouse diversity panel, MDP) as a QTL mapping population. The use of the MDP population has many advantages relative to traditional F(2) mapping populations, including increased phenotypic diversity, a higher recombination frequency, and the ability to collect genotype and phenotype data in community databases. However, these methods are complicated by population structure inherent in the MDP and the lack of an analytical framework to assess statistical power. To address these issues, we measured gene expression levels in hypothalamus across the MDP. We then mapped these phenotypes as quantitative traits with our association algorithm, resulting in a large set of expression QTL (eQTL). We utilized these eQTL, and specifically cis-eQTL, to develop a novel nonparametric method for association analysis in structured populations like the MDP. These eQTL data confirmed that the MDP is a suitable mapping population for QTL discovery and that eQTL results can serve as a gold standard for relative measures of statistical power.


Assuntos
Técnicas Genéticas , Genoma , Endogamia , Dinâmica Populacional , Análise de Variância , Animais , Análise por Conglomerados , Expressão Gênica , Hipotálamo/metabolismo , Camundongos , Locos de Características Quantitativas/genética , Estatísticas não Paramétricas
4.
Proc Natl Acad Sci U S A ; 103(9): 3153-8, 2006 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-16492761

RESUMO

Rapid quantitative methods for characterizing small molecules, peptides, proteins, or RNAs in a broad array of cellular assays would allow one to discover new biological activities associated with these molecules and also provide a more comprehensive profile of drug candidates early in the drug development process. Here we describe a robotic system, termed the automated compound profiler, capable of both propagating a large number of cell lines in parallel and assaying large collections of molecules simultaneously against a matrix of cellular assays in a highly reproducible manner. To illustrate its utility, we have characterized a set of 1,400 kinase inhibitors in a panel of 35 activated tyrosine-kinase-dependent cellular assays in dose-response format in a single experiment. Analysis of the resulting multidimensional dataset revealed subclusters of both inhibitors and kinases with closely correlated activities. The approach also identified activities for the p38 inhibitor BIRB796 and the dual src/abl inhibitor BMS-354825 and exposed the expected side activities for Glivec/STI571, including cellular inhibition of c-kit and platelet-derived growth factor receptor. This methodology provides a powerful tool for unraveling the cellular biology and molecular pharmacology of both naturally occurring and synthetic chemical diversity.


Assuntos
Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Robótica/métodos , Animais , Automação , Linhagem Celular , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos/métodos , Camundongos , Fosfotransferases/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Reprodutibilidade dos Testes , Relação Estrutura-Atividade , Fatores de Tempo
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