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1.
ChemMedChem ; 8(2): 313-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23307663

RESUMO

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Descoberta de Drogas/métodos , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bases de Dados de Produtos Farmacêuticos , Células Hep G2 , Ensaios de Triagem em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
2.
J Biomol Screen ; 17(5): 641-50, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22337655

RESUMO

Microsomal prostaglandin E synthase-1 (mPGES-1) represents an attractive target for the treatment of rheumatoid arthritis and pain, being upregulated in response to inflammatory stimuli. Biochemical assays for prostaglandin E synthase activity are complicated by the instability of the substrate (PGH(2)) and the challenge of detection of the product (PGE(2)). A coupled fluorescent assay is described for mPGES-1 where PGH(2) is generated in situ using the action of cyclooxygenase 2 (Cox-2) on arachidonic acid. PGE(2) is detected by coupling through 15-prostaglandin dehydrogenase (15-PGDH) and diaphorase. The overall coupled reaction was miniaturized to 1536-well plates and validated for high-throughput screening. For compound progression, a novel high-throughput mass spectrometry assay was developed using the RapidFire platform. The assay employs the same in situ substrate generation step as the fluorescent assay, after which both PGE(2) and a reduced form of the unreacted substrate were detected by mass spectrometry. Pharmacology and assay quality were comparable between both assays, but the mass spectrometry assay was shown to be less susceptible to interference and false positives. Exploiting the throughput of the fluorescent assay and the label-free, direct detection of the RapidFire has proved to be a powerful lead discovery strategy for this challenging target.


Assuntos
Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes/química , Ensaios de Triagem em Larga Escala/métodos , Oxirredutases Intramoleculares/antagonistas & inibidores , Espectrometria de Massas/métodos , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Corantes Fluorescentes/metabolismo , Humanos , Concentração Inibidora 50 , Oxirredutases Intramoleculares/metabolismo , Prostaglandina-E Sintases
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