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1.
The rapidly changing developments in genomics and combinatorial chemistry, generating new drug targets and large numbers of compounds, have caused a revolution in high-throughput screening technologies. Key to this revolution has been the introduction of robotics and automation, together with new biological assay technologies (e.g., homogeneous time resolved fluorescence). With ever increasing workloads, together with economic and logistical constraints, miniaturisation is rapidly becoming essential for the future of high-throughput screening and combinatorial chemistry. This is evident from the introduction of high-density microtitre plates, small volume liquid handling robots and associated detection technology.  相似文献   

2.
Directed or exploratory drug development programs constantly seek robust screening platforms for the high fidelity identification and validation of potential targets. Small-molecule microarrays (SMMs) have risen to this call by elegantly forging the capability of combinatorial chemistry in producing myriad compounds with the powerful throughput afforded by microarrays. This synergism offers scientists a versatile tool for rapid compound analysis and discovery. Microarrays of small molecules have already been successfully applied in important areas ranging from protein profiling to the discovery of therapeutic leads. Recent interesting developments towards improved immobilization strategies and library creation methods, together with novel advances herein described, have set the stage for SMMs to take on wider and more routine applications in academia and industry. As a rapidly maturing technology, SMMs pave the way forward in high-throughput exploration, both in the identification of biologically significant natural and synthetic small molecules and in harnessing their vast potential towards medicinal and diagnostic applications.  相似文献   

3.
A new armoury of protein purification tools is required to support rapid advances in high-throughput genomics and proteomics, which are predicted to lead to the discovery, isolation, characterisation and manufacture of a number of new biopharmaceutical proteins. Computer-aided molecular design, combinatorial (bio)chemistry and high-throughput screening techniques are now being exploited to identify highly selective ligands for use in the purification of these proteins by affinity chromatography.  相似文献   

4.
The past year has seen significant advances in the reduction to practice of inkjet dispensing technology in drug discovery applications. Although much of the work in this area has been done by relatively few ‘early innovators’, broader acceptance of the feasibility of the use of inkjet dispensing is on the rise. Of the three main areas of drug discovery — genomics, high-throughput screening, and combinatorial chemistry — high-throughput screening has had the most applications to date. The burgeoning field of genomics has seen rapid incorporation of technologies that enable miniaturization of gene expression experiments. Inkjet dispensing has a clear role in this effort. Finally, as the miniaturization needs of combinatorial chemistry become more clear, inkjet dispensing technology will potentially play a role.  相似文献   

5.
从50年前英国科学家解析出第一个蛋白质晶体结构以来,蛋白质晶体学历经数个里程碑式的发展,已经成为一门成熟的高科技学科,是结构生物学的主要研究手段。近年来结构生物学发展迅速并和其他学科相互渗透交叉,特别是受到结构基因组学等热点学科的极大带动。作为结构生物学的基本手段和技术,蛋白质晶体学从解析简单的蛋白质三维结构延伸到解决各类生物大分子及复合物结构,并更加注重研究结构与功能之间的相互关系,派生出诸如基于结构的药物设计等应用性很强的分支。生物技术及计算机技术的飞速发展,尤其是高通量技术在生物学领域的应用,为蛋白质晶体学带来了全新的概念和更加广阔的前景。文章将主要介绍蛋白质晶体学技术的一些历史发展以及对未来的展望。  相似文献   

6.
AimsAccurate knowledge of molecular structure is a prerequisite for rational drug design. This review examines the role of X-ray crystallography in providing the required structural information and advances in the field of X-ray crystallography that enhance or expand its role.Main methodsX-ray crystallography of new drugs candidates and intermediates can provide valuable information of new syntheses and parameters for quantitative structure activity relationships (QSAR).Key findingsCrystallographic studies play a vital role in many disciplines including materials science, chemistry, pharmacology, and molecular biology. X-ray crystallography is the most comprehensive technique available to determine molecular structure. A requirement for the high accuracy of crystallographic structures is that a ‘good crystal’ must be found, and this is often the rate-limiting step. In the past three decades developments in detectors, increases in computer power, and powerful graphics capabilities have contributed to a dramatic increase in the number of materials characterized by X-ray crystallography. More recently the advent of high-throughput crystallization techniques has enhanced our ability to produce that one good crystal required for crystallographic analysis.SignificanceContinuing advances in all phases of a crystallographic study have expanded the ranges of samples which can be analyzes by X-ray crystallography to include larger molecules, smaller or weakly diffracting crystals, and twinned crystals.  相似文献   

7.
Phosphors are key materials in fluorescent lighting, displays, x-ray scintillation, etc. The rapid development of modern photonic technologies, e.g., mercury-free lamps, flat panel displays, CT-detector array, etc., demands timely discovery of advanced phosphors. To this end, a combinatorial approach has been developed and applied to accelerated experimental search of advanced phosphors and scintillators. Phosphor libraries can be made in both thin film and powder form, using masking strategies and liquid dispensing systems, respectively. High-density libraries with 100 to 1000 discrete phosphor compositions on a 1"-square substrate can be made routinely. Both compositions and synthesis temperatures can be screened in a high-throughput mode. In this article, details on the existing methods of combinatorial synthesis and screening of phosphors will be reported with examples. These methods are generic tools for application of combinatorial chemistry in the discovery of other solid state materials. A few highly efficient phosphors discovered with combinatorial methods have been reproduced in bulk form and their luminescent properties measured.  相似文献   

8.
When combinatorial chemistry was introduced 13 years ago, the expectations were high for the delivery of results, particularly in the pharmaceutical industry. However, combinatorial chemistry was implemented independently of the application for which the products were going to be used. Resins developed only for efficient solid-phase synthesis were used and products were employed in existing assays developed for traditional solution studies. There was almost no assay or technology development and the use of real combinatorial methods soon had to give way to high-throughput synthesis and traditional screening. However, during recent years more sophisticated resins and assay techniques have been developed that may result in a second and more successful implementation of real integrated combinatorial chemistry. The first in this line of new developments is the 'one bead two compound' assay, in which the resin bead in addition to a combinatorial library member contains a reporter compound that can act as a beacon to monitor the activity of the library member. This powerful concept can be generally applied in all fields of combinatorial chemistry including drug, catalysts and material development.  相似文献   

9.
Structural proteomics is one of the powerful research areas in the postgenomic era, elucidating structure-function relationships of uncharacterized gene products based on the 3D protein structure. It proposes biochemical and cellular functions of unannotated proteins and thereby identifies potential drug design and protein engineering targets. Recently, a number of pioneering groups in structural proteomics research have achieved proof of structural proteomic theory by predicting the 3D structures of hypothetical proteins that successfully identified the biological functions of those proteins. The pioneering groups made use of a number of techniques, including NMR spectroscopy, which has been applied successfully to structural proteomics studies over the past 10 years. In addition, advances in hardware design, data acquisition methods, sample preparation and automation of data analysis have been developed and successfully applied to high-throughput structure determination techniques. These efforts ensure that NMR spectroscopy will become an important methodology for performing structural proteomics research on a genomic scale. NMR-based structural proteomics together with x-ray crystallography will provide a comprehensive structural database to predict the basic biological functions of hypothetical proteins identified by the genome projects.  相似文献   

10.
Mass spectrometry (MS) is an important tool in modern protein chemistry. In proteome analyses the expression of hundreds or thousands of proteins can be monitored at the same time. First, complex protein mixtures are separated by two-dimensional gel electrophoresis (2-DE) and then individual proteins are identified by using MS followed by database searches. Recent developments in this field have made it possible to do automated, high-throughput protein identification that is needed in proteome analyses. MS can also be used to characterize post-translational modifications in proteins and to study protein complexes. This review will introduce the current MS methods used in proteome studies, and discuss their advantages and disadvantages. New instrumental MS developments are also presented that are useful in these analyses.  相似文献   

11.
Flow NMR techniques are now well accepted and widely used in many areas of drug discovery. Although natural-product-, rational-drug-design-, and NMR-screening-programs have begun to use flow NMR more routinely, flow NMR has not yet gained widespread acceptance in combinatorial chemistry, even though it has been shown to be a potentially useful tool. Recent developments in DI-NMR, FIA-NMR, and LC-NMR will help flow NMR eventually gain a wider acceptance within combinatorial chemistry. These developments include LC-NMR-MS instrumentation, flow probe improvements, new pulse sequences, improved automation of NMR data analysis, and the application of flow NMR to related fields in drug discovery.  相似文献   

12.
Gavin MacBeath 《Genome biology》2001,2(6):comment2005.1-comment20056
Chemical genomics requires continued advances in combinatorial chemistry, protein biochemistry, miniaturization, automation, and global profiling technology. Although innovation in each of these areas can come from individual academic labs, it will require large, well-funded centers to integrate these components and freely distribute both data and reagents.  相似文献   

13.
Recent advances in metabolic engineering have enabled microbial factories to compete with conventional processes for producing fuels and chemicals. Both rational and combinatorial approaches coupled with synthetic and systematic tools play central roles in metabolic engineering to create and improve a selected microbial phenotype. Compared to knowledge-based rational approaches, combinatorial approaches exploiting biological diversity and high-throughput screening have been demonstrated as more effective tools for improving various phenotypes of interest. In particular, identification of unprecedented targets to rewire metabolic circuits for maximizing yield and productivity of a target chemical has been made possible. This review highlights general principles and the features of the combinatorial approaches using various libraries to implement desired phenotypes for strain improvement. In addition, recent applications that harnessed the combinatorial approaches to produce biofuels and biochemicals will be discussed.  相似文献   

14.
The crystallization facility of the TB Structural Genomics Consortium, one of nine NIH-sponsored structural genomics pilot projects, employs a combinatorial random sampling technique in high-throughput crystallization screening. Although data are still sparse and a comprehensive analysis cannot be performed at this stage, preliminary results appear to validate the random-screening concept. A discussion of statistical crystallization data analysis aims to draw attention to the need for comprehensive and valid sampling protocols. In view of limited overlap in techniques and sampling parameters between the publicly funded high-throughput crystallography initiatives, exchange of information should be encouraged, aiming to effectively integrate data mining efforts into a comprehensive predictive framework for protein crystallization.  相似文献   

15.
During the past year, electron crystallography of membrane proteins has provided structural insights into the mechanism of several different transporters and into their interactions with lipid molecules within the bilayer. From a technical perspective there have been important advances in high-throughput screening of crystallization trials and in automated imaging of membrane crystals with the electron microscope. There have also been key developments in software, and in molecular replacement and phase extension methods designed to facilitate the process of structure determination.  相似文献   

16.
The pace of data accumulation in glycobiology has lately rapidly increased, largely due to high-throughput technologies. In this increasingly data-rich environment, computer science started to play a central role in handling the data, extracting significant biological information, and probing the missing parts of the 'scenery' by prediction, modelling or simulation. Investigating and comparing glycomes by bioinformatics and structural methods has great practical value and sharply increased in popularity in the past couple of years. In this context, advances have also been made with regard to structural aspects of protein N-glycosylation and consequences for glycoprotein folding. In these areas, however, an approach that integrates glycobiology with protein science is necessary.  相似文献   

17.
Life in the fast lane for protein crystallization and X-ray crystallography   总被引:3,自引:0,他引:3  
The common goal for structural genomic centers and consortiums is to decipher as quickly as possible the three-dimensional structures for a multitude of recombinant proteins derived from known genomic sequences. Since X-ray crystallography is the foremost method to acquire atomic resolution for macromolecules, the limiting step is obtaining protein crystals that can be useful of structure determination. High-throughput methods have been developed in recent years to clone, express, purify, crystallize and determine the three-dimensional structure of a protein gene product rapidly using automated devices, commercialized kits and consolidated protocols. However, the average number of protein structures obtained for most structural genomic groups has been very low compared to the total number of proteins purified. As more entire genomic sequences are obtained for different organisms from the three kingdoms of life, only the proteins that can be crystallized and whose structures can be obtained easily are studied. Consequently, an astonishing number of genomic proteins remain unexamined. In the era of high-throughput processes, traditional methods in molecular biology, protein chemistry and crystallization are eclipsed by automation and pipeline practices. The necessity for high-rate production of protein crystals and structures has prevented the usage of more intellectual strategies and creative approaches in experimental executions. Fundamental principles and personal experiences in protein chemistry and crystallization are minimally exploited only to obtain “low-hanging fruit” protein structures. We review the practical aspects of today's high-throughput manipulations and discuss the challenges in fast pace protein crystallization and tools for crystallography. Structural genomic pipelines can be improved with information gained from low-throughput tactics that may help us reach the higher-bearing fruits. Examples of recent developments in this area are reported from the efforts of the Southeast Collaboratory for Structural Genomics (SECSG).  相似文献   

18.
News in Brief     
Protein microarrays are versatile tools for parallel, miniaturized screening of binding events involving large numbers of immobilized proteins in a time- and cost-effective manner. They are increasingly applied for high-throughput protein analyses in many research areas, such as protein interactions, expression profiling and target discovery. While conventionally made by the spotting of purified proteins, recent advances in technology have made it possible to produce protein microarrays through in situ cell-free synthesis directly from corresponding DNA arrays. This article reviews recent developments in the generation of protein microarrays and their applications in proteomics and diagnostics.  相似文献   

19.
Phage display for engineering and analyzing protein interaction interfaces   总被引:8,自引:3,他引:5  
Phage display is the longest-standing platform among molecular display technologies. Recent developments have extended its utility to proteins that were previously recalcitrant to phage display. The technique has played a dominant role in forming the field of synthetic binding protein engineering, where novel interfaces have been generated from libraries built using antibody fragment frameworks and also alternative scaffolds. Combinatorial methods have also been developed for the rapid analysis of binding energetics across protein interfaces. The ability to rapidly select and analyze binding interfaces, and compatibility with high-throughput methods under diverse conditions, makes it likely that the combination of phage display and synthetic combinatorial libraries will prove to be the method of choice for synthetic binding protein engineering for broad applications.  相似文献   

20.
The sequence infrastructure that has arisen through large-scale genomic projects dedicated to protein analysis, has provided a wealth of information and brought together scientists and institutions from all over the world. As a consequence, the development of novel technologies and methodologies in proteomics research is helping to unravel the biochemical and physiological mechanisms of complex multivariate diseases at both a functional and molecular level. In the late sixties, when X-ray crystallography had just been established, the idea of determining protein structure on an almost universal basis was akin to an impossible dream or a miracle. Yet only forty years after, automated protein structure determination platforms have been established. The widespread use of robotics in protein crystallography has had a huge impact at every stage of the pipeline from protein cloning, over-expression, purification, crystallization, data collection, structure solution, refinement, validation and data management- all of which have become more or less automated with minimal human intervention necessary. Here, recent advances in protein crystal structure analysis in the context of structural genomics will be discussed. In addition, this review aims to give an overview of recent developments in high throughput instrumentation, and technologies and strategies to accelerate protein structure/function analysis.  相似文献   

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