RESUMO
HTS remains at the core of the drug discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry, engineering, and informatics. This requires careful consideration of many options and variables, starting with the choice of screening strategy and ending with the discovery of lead compounds. At every step in this process, there are decisions to be made that can greatly impact the outcome of the HTS effort, to the point of making it a success or a failure. Although specific guidelines should be established to ensure that the screening assay reaches an acceptable level of quality, many choices require pragmatism and the ability to compromise opposing forces.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Animais , Bioquímica/métodos , Técnicas Citológicas/métodos , Ensaios Enzimáticos/métodos , Humanos , Razão Sinal-Ruído , Estudos de Validação como AssuntoRESUMO
High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.
Assuntos
Pesquisa Biomédica , Avaliação Pré-Clínica de Medicamentos , Animais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Humanos , Bibliotecas de Moléculas PequenasRESUMO
High throughput screening (HTS) is at the core of the drug discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry, engineering, and informatics. This requires careful analysis of many variables, starting with the choice of assay target and ending with the discovery of lead compounds. At every step in this process, there are decisions to be made that can greatly impact the outcome of the HTS effort, to the point of making it a success or a failure. Although specific guidelines should be established to insure that the screening assay reaches an acceptable level of quality, many choices require pragmatism and the ability to compromise opposing forces.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Células Cultivadas , HumanosRESUMO
HTS is at the core of the drug discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry, engineering, and informatics. This requires careful analysis of many variables, starting with the choice of assay target and ending with the discovery of lead compounds. At every step in this process, there are decisions to be made that can greatly impact the outcome of the HTS effort, to the point of making it a success or a failure. Although specific guidelines should be established to ensure that the screening assay reaches an acceptable level of quality, many choices require pragmatism and the ability to compromise opposing forces.
Assuntos
Bioensaio/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Células Cultivadas , Humanos , Reprodutibilidade dos TestesRESUMO
N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit models of ear edema and neutropenia.
Assuntos
Anti-Inflamatórios/síntese química , Compostos de Fenilureia/síntese química , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ligação Competitiva , Células CHO , Cálcio/metabolismo , Quimiocina CXCL1 , Quimiocinas , Fatores Quimiotáticos , Quimiotaxia , Cricetinae , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/tratamento farmacológico , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-8 , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/fisiologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Coelhos , Ensaio Radioligante , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-AtividadeRESUMO
HTS is at the core of the drug-discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry, engineering, and informatics. This requires careful analysis of many variables, starting with the choice of assay target and ending with the discovery of lead compounds. At every step in this process, there are decisions to be made that can greatly impact the outcome of the HTS effort, to the point of making it a success or a failure. Although specific guidelines can be established to ensure that the screening assay reaches an acceptable level of quality, many choices require pragmatism and the ability to compromise opposing forces.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Desenho de Fármacos , Inibidores Enzimáticos , Enzimas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Indicadores e Reagentes , Biologia Molecular/métodos , Receptores de Superfície Celular/análise , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Espectrometria de Fluorescência , Especificidade por SubstratoRESUMO
The thrust of early drug discovery in recent years has been toward the configuration of homogeneous miniaturized assays. This has allowed organizations to contain costs in the face of exponential increases in the number of screening assays that need to be run to remain competitive. Miniaturization brings with it an increasing dependence on instrumentation, which over the past several years has seen the development of nanodispensing capability and sophisticated detection strategies. To maintain confidence in the data generated from miniaturized assays, it is critical to ensure that both compounds and reagents have been delivered as expected to the target wells. The authors have developed a standard operating procedure for liquid-handling quality control that has enabled them to evaluate performance on 2 levels. The first level provides for routine daily testing on existing instrumentation, and the second allows for more rigorous testing of new dispensing technologies. The procedure has shown itself to be useful in identifying both method programming and instrumentation performance shortcomings and has provided a means to harmonizing instrumentation usage by assay development and screening groups. The goal is that this type of procedure be used for facilitating the exchange of liquid handler performance data across the industry.
