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1.
ACS Comb Sci ; 21(6): 437-444, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-30939240

RESUMO

This is a report on the early years of combinatorial materials science and technology. High-throughput technologies (HTTs) are found in life- and materials-science laboratories. Although HTTs have long been the standard in life sciences in academia as well as in industry, HTTs in materials science have become the standard in industry but not in academia. In life science, successful drugs developed with HTTs have been reported, but there is no information on successful materials developed with HTTs that have made it to the market. Some initial development of HTTs in materials science is summarized, especially early applications of artificial intelligence. This outlook attempts to summarize the development of combinatorial materials sciences from the early years to today.


Assuntos
Ensaios de Triagem em Larga Escala , Ciência dos Materiais , Catálise , Avaliação Pré-Clínica de Medicamentos/história , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Ensaios de Triagem em Larga Escala/história , Ensaios de Triagem em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/normas , História do Século XX , História do Século XXI , Indústrias/história , Indústrias/métodos , Ciência dos Materiais/história , Ciência dos Materiais/métodos , Ciência dos Materiais/normas
2.
Philos Trans A Math Phys Eng Sci ; 377(2147): 20180422, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31030650

RESUMO

Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as 'warm spots' for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue 'Fifty years of synchrotron science: achievements and opportunities'.


Assuntos
Descoberta de Drogas/história , Síncrotrons/história , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Ensaios de Triagem em Larga Escala/história , Ensaios de Triagem em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/tendências , História do Século XX , História do Século XXI , Humanos , Modelos Moleculares , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Peptídeo Sintases/química , Peptídeo Sintases/metabolismo
3.
Methods ; 158: 2-11, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30659874

RESUMO

Multiplexed analysis has the advantage of allowing for simultaneous detection of multiple analytes in a single reaction vessel which reduces time, labor, and cost as compared to single-reaction-based detection methods. Microsphere-based suspension array technologies, such as the Luminex® xMAP® system, offer high-throughput detection of both protein and nucleic acid targets in multiple assay chemistries. After Luminex's founding in 1995, it quickly became the leader in bead-based multiplexing solutions. Today, xMAP Technology is the most widely adopted bead-based multiplexing platform with over 35,000 peer-reviewed publications, an installed base of approximately 15,500 instruments, and over 70 Luminex Partners offering more than 1300 research use kits as well as custom assay solutions. Because of the open architecture of the xMAP platform it has been implemented in a variety of applications that range from transplant medicine, biomarker discovery and validation, pathogen detection, drug discovery, vaccine development, personalized medicine, neurodegeneration, and cancer research.


Assuntos
Ensaios de Triagem em Larga Escala/história , Microesferas , Biomarcadores/análise , Ensaios Enzimáticos/história , Ensaios Enzimáticos/instrumentação , Ensaios Enzimáticos/métodos , Ensaios Enzimáticos/tendências , Citometria de Fluxo/história , Citometria de Fluxo/instrumentação , Citometria de Fluxo/métodos , Citometria de Fluxo/tendências , Ensaios de Triagem em Larga Escala/instrumentação , Ensaios de Triagem em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/tendências , História do Século XX , História do Século XXI , Humanos , Imunoensaio/história , Imunoensaio/instrumentação , Imunoensaio/métodos , Imunoensaio/tendências , Fenômenos Magnéticos , Hibridização de Ácido Nucleico
5.
J Lab Autom ; 21(1): 76-89, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26169025

RESUMO

Since the adoption of Labcyte Echo Acoustic Droplet Ejection (ADE) technology by AstraZeneca in 2005, ADE has become the preferred method for compound dosing into both biochemical and cell-based assays across AstraZeneca research and development globally. The initial implementation of Echos and the direct dosing workflow provided AstraZeneca with a unique set of challenges. In this article, we outline how direct Echo dosing has evolved over the past decade in AstraZeneca. We describe the practical challenges of applying ADE technology to 96-well, 384-well, and 1536-well assays and how AstraZeneca developed and applied software and robotic solutions to generate fully automated and effective cell-based assay workflows.


Assuntos
Tecnologia Biomédica/métodos , Técnicas Citológicas/métodos , Ensaios de Triagem em Larga Escala/métodos , Acústica , Fenômenos Bioquímicos , Tecnologia Biomédica/história , Tecnologia Biomédica/instrumentação , Técnicas Citológicas/história , Técnicas Citológicas/instrumentação , Ensaios de Triagem em Larga Escala/história , Ensaios de Triagem em Larga Escala/instrumentação , História do Século XXI , Soluções
6.
Crit Rev Oncol Hematol ; 96(2): 274-307, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26427785

RESUMO

It is today indisputable that great progresses have been made in our molecular understanding of cancer cells, but an effective implementation of such knowledge into dramatic cancer-cures is still belated and yet desperately needed. This review gives a snapshot at where we stand today in this search for cancer understanding and definitive treatments, how far we have progressed and what are the major obstacles we will have to overcome both technologically and for disease modelling. In the first part, promising 3rd/4th Generation Sequencing Technologies will be summarized (particularly IonTorrent and OxfordNanopore technologies). Cancer modelling will be then reviewed from its origin in XIX Century Germany to today's NGS applications for cancer understanding and therapeutic interventions. Developments after Molecular Biology revolution (1953) are discussed as successions of three phases. The first, PH1, labelled "Clonal Outgrowth" (from 1960s to mid 1980s) was characterized by discoveries in cytogenetics (Nowell, Rowley) and viral oncology (Dulbecco, Bishop, Varmus), which demonstrated clonality. Treatments were consequently dominated by a "cytotoxic eradication" strategy with chemotherapeutic agents. In PH2, (from the mid 1980s to our days) the description of cancer as "Gene Networks" led to targeted-gene-therapies (TGTs). TGTs are the focus of Section 3: in view of their apparent failing (Ephemeral Therapies), alternative strategies will be discussed in review part II (particularly cancer immunotherapy, CIT). Additional Pitfalls impinge on the concepts of tumour heterogeneity (inter/intra; ITH). The described pitfalls set the basis for a new phase, PH3, which is called "NGS Era" and will be also discussed with ten emerging cancer models in the Review 2nd part.


Assuntos
Ensaios de Triagem em Larga Escala/história , Ensaios de Triagem em Larga Escala/métodos , Neoplasias/história , História do Século XX , História do Século XXI , Humanos
7.
Methods Mol Biol ; 1272: 3-19, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25563173

RESUMO

The existence of cellular receptors, a group of specialized biomolecules to which endogenous and exogenous compounds bind and exert an effect, is one of the most exciting aspects of cell biology. Among the different receptor types recognized today, G-protein-coupled receptors (GPCRs) constitute, undoubtedly, one of the most important classes, in part due to their versatility, but particularly, due to their central role in a multitude of physiological states. The unveiling of GPCR function and mode of action is a challenging task that prevails until our days, as the full potential of these receptors is far from being established. Such an undertaking calls for a joint effort of multidisciplinary teams that must combine state-of-the-art technologies with in-depth knowledge of cell biology to probe such specialized molecules. This review provides a concise coverage of the scientific progress that has been made in GPCR research to provide researchers with an updated overview of the field. A brief outline of the historical breakthroughs is followed by a discussion of GPCR signaling mechanisms and by a description of the role played by assay technologies.


Assuntos
Ensaios de Triagem em Larga Escala/história , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Bioensaio/história , Clonagem Molecular , Cristalografia por Raios X/história , Expressão Gênica , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Ensaio Radioligante/história , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/história
9.
J Biomol Screen ; 15(7): 720-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20639498

RESUMO

High-content screening (HCS) was introduced in 1997 based on light microscope imaging technologies to address the need for an automated platform that could analyze large numbers of individual cells with subcellular resolution using standard microplates. Molecular specificity based on fluorescence was a central element of the platform taking advantage of the growing list of reagent classes and the ability to multiplex. In addition, image analysis coupled to data management, data mining, and data visualization created a tool that focused on biological information and knowledge to begin exploring the functions of genes identified in the genomics revolution. This overview looks at the development of HCS, the evolution of the technologies, and the market up to the present day. In addition, the options for adopting uniform definitions is suggested along with a perspective on what advances are needed to continue building the value of HCS in biomedical research, drug discovery, and development and diagnostics.


Assuntos
Avaliação Pré-Clínica de Medicamentos/história , Ensaios de Triagem em Larga Escala/história , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , História do Século XX , História do Século XXI , Processamento de Imagem Assistida por Computador
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