Current Opinion in Drug Discovery & Development

Public chemical compound databases.

Publication Date: 2008 May PMID: 18428094
Authors: Williams, A. J.
Journal: Curr Opin Drug Discov Devel

The internet has rapidly become the first port of call for all information searches. The increasing array of chemistry-related resources that are now available provides chemists with a direct path to the information that was previously accessed via library services and was limited by commercial and costly resources. The diversity of the information that can be accessed online is expanding at a dramatic rate, and the support for publicly available resources offers significant opportunities in terms of the benefits to science and society. While the data online do not generally meet the quality standards of manually curated sources, there are efforts underway to gather scientists together and 'crowdsource' an improvement in the quality of the available data. This review discusses the types of public compound databases that are available online and provides a series of examples. Focus is also given to the benefits and disruptions associated with the increased availability of such data and the integration of technologies to data mine this information.

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Software for rapid prototyping in the pharmaceutical and biotechnology industries.

Publication Date: 2008 May PMID: 18428093
Authors: Kappler, M. A.
Journal: Curr Opin Drug Discov Devel

The automation of drug discovery methods continues to develop, especially techniques that process information, represent workflow and facilitate decision-making. The magnitude of data and the plethora of questions in pharmaceutical and biotechnology research give rise to the need for rapid prototyping software. This review describes the advantages and disadvantages of three solutions: Competitive Workflow, Taverna and Pipeline Pilot. Each of these systems processes large amounts of data, integrates diverse systems and assists novice programmers and human experts in critical decision-making steps.

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Scientific workflows as productivity tools for drug discovery.

Publication Date: 2008 May PMID: 18428092
Authors: Shon, J. - Ohkawa, H. - Hammer, J.
Journal: Curr Opin Drug Discov Devel

Large pharmaceutical companies annually invest tens to hundreds of millions of US dollars in research informatics to support their early drug discovery processes. Traditionally, most of these investments are designed to increase the efficiency of drug discovery. The introduction of do-it-yourself scientific workflow platforms has enabled research informatics organizations to shift their efforts toward scientific innovation, ultimately resulting in a possible increase in return on their investments. Unlike the handling of most scientific data and application integration approaches, researchers apply scientific workflows to in silico experimentation and exploration, leading to scientific discoveries that lie beyond automation and integration. This review highlights some key requirements for scientific workflow environments in the pharmaceutical industry that are necessary for increasing research productivity. Examples of the application of scientific workflows in research and a summary of recent platform advances are also provided.

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Recent trends in library design: 'Rational design' revisited.

Publication Date: 2008 May PMID: 18428091
Authors: Schnur, D. M.
Journal: Curr Opin Drug Discov Devel

Diversity has historically played a critical role in the design of combinatorial libraries, screening sets and corporate collections for lead discovery. Large library design dominated the field of lead discovery in the 1990s, with design methods ranging from arbitrary and property-based reagent selection to product-based approaches. Over time, however, there has been a downward trend in library size as the genomics revolution and the increasing availability of target protein structures from X-ray crystallography and homology modeling have increased the volume of information concerning desired targets. Concurrently, computing grids and CPU clusters have facilitated the development of structure-based tools that are able to screen hundreds of thousands of molecules. Smaller, 'smarter' combinatorial and focused parallel libraries have replaced the unfocused large libraries in the drug design paradigm of the 21st century. While diversity continues to play a role in lead discovery, the focus of current library design methods has shifted to scaffold design and bio-isostere searching, with a greatly needed emphasis on synthetic feasibility.

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Recent developments in de novo design and scaffold hopping.

Publication Date: 2008 May PMID: 18428090
Authors: Mauser, H. - Guba, W.
Journal: Curr Opin Drug Discov Devel

This review covers the developments in the fields of de novo ligand design and scaffold hopping since 2006. De novo ligand design was introduced in 1991 as a purely structure-based method to suggest ligands for synthesis and was later augmented by ligand-based approaches. Both structure-based and ligand-based methods identify pharmacophores, as well as shape constraints, and subsequently match these with complementary features embedded into small-molecule topologies. Recently, significant attention has been paid to de novo ligand design in combination with biophysical fragment screening and X-ray structure elucidation. Scaffold hopping has evolved from a niche application of de novo design into a rapidly expanding suite of different software tools, which are used extensively in the pharmaceutical industry.

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The use of protein-ligand interaction fingerprints in docking.

Publication Date: 2008 May PMID: 18428089
Authors: Brewerton, S. C.
Journal: Curr Opin Drug Discov Devel

The use of structure-based virtual screening to predict small-molecule binding in a target active site is an increasingly popular approach in drug discovery programs. As the number of structures of protein-ligand complexes in public and proprietary databases grow, it is important to incorporate prior structural knowledge of ligand binding into virtual screening experiments. The structural interaction fingerprint (SIFt) approach aims to capture a 1D representation of the interactions between ligand and protein either in complexes of known structure or in docked poses. This review describes recent developments in the use of the SIFt in rescoring docked ligand poses in virtual screening.

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The synergy between combinatorial chemistry and high-throughput screening.

Publication Date: 2008 May PMID: 18428088
Authors: Diller, D. J.
Journal: Curr Opin Drug Discov Devel

Despite the initial promise of combinatorial chemistry, particularly large library combinatorial chemistry, to greatly accelerate drug discovery, this approach has not been fully utilized as a means to build the compound collections of pharmaceutical and biotechnology companies. This review highlights some of the strengths of large library combinatorial chemistry as a means of generating molecules for lead discovery, such as providing rich and robust structure-activity relationships around each hit series. The challenges and concepts emerging from traditional high-throughput screening and fragment-based drug design, how these methods influence the design of large combinatorial libraries and the interpretation of the ensuing high-throughput screening data are also highlighted.

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Prioritizing hits from phenotypic high-content screens.

Publication Date: 2008 May PMID: 18428087
Authors: Low, J. - Stancato, L. - Lee, J. - Sutherland, J. J.
Journal: Curr Opin Drug Discov Devel

In the past decade, advances in the field of high-content screening (HCS) have provided researchers with a powerful new screening tool to observe treatment effects on multiple experimental parameters. While extremely useful, HCS has resulted in the collection of large datasets of increased complexity that require intensive analysis. Recently, approaches have been developed to analyze multi-parametric HCS data more completely and, when used in conjunction with RNA interference, target-based biochemistry and structural analysis, these approaches have begun to unlock the potential of this screening format in aiding drug discovery. This review illustrates how the combination of these technologies has been used to successfully drive the drug discovery process.

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Which aspects of HTS are empirically correlated with downstream success?

Publication Date: 2008 May PMID: 18428086
Authors: Bender, A. - Bojanic, D. - Davies, J. W. - Crisman, T. J. - Mikhailov, D. - Scheiber, J. - Jenkins, J. L. - Deng, Z. - Hill, W. A. - Popov, M. - Jacoby, E. - Glick, M.
Journal: Curr Opin Drug Discov Devel

High-throughput screening (HTS) is a well-established hit-finding approach used in the pharmaceutical industry. In this article, recent experience at Novartis with respect to factors influencing the success of HTS campaigns is discussed. An inherent measure of HTS quality could be defined by the assay Z and Z' factors, the number of hits and their biological potencies; however, such measures of quality do not always correlate with the advancement of hits to the later stages of drug discovery. Also, for many target classes, such as kinases, it is easy to identify hits, but, as a result of selectivity, intellectual property and other issues, the projects do not result in lead declarations. In this article, HTS success is defined as the fraction of HTS campaigns that advance into the later stages of drug discovery, and the major influencing factors are examined. Interestingly, screening compounds in individual wells or in mixtures did not have a major impact on the HTS success and, equally interesting, there was no difference in the progression rates of biochemical and cell-based assays. Particular target types, assay technologies, structure-activity relationships and powder availability had a much greater impact on success as defined above. In addition, significant mutual dependencies can be observed - while one assay format works well with one target type, this situation might be completely reversed for a combination of the same readout technology with a different target type. The results and opinions presented here should be regarded as groundwork, and a plethora of factors that influence the fate of a project, such as biophysical measurements, chemical attractiveness of the hits, strategic reasons and safety pharmacology, are not covered here. Nonetheless, it is hoped that this information will be used industry-wide to improve success rates in terms of hits progressing into exploratory chemistry and beyond. The support that can be obtained from new in silico approaches to phase transitions are also described, along with the gaps they are designed to fill.

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Mathematical biodescriptors of proteomics maps: Background and applications.

Publication Date: 2008 May PMID: 18428085
Authors: Basak, S. C. - Gute, B. D.
Journal: Curr Opin Drug Discov Devel

This article reviews recent developments in the formulation and application of biodescriptors to characterize proteomics maps. Such biodescriptors can be derived by applying techniques from discrete mathematics (graph theory, linear algebra and information theory). This review focuses on the development of biodescriptors for proteomics maps derived from 2D gel electrophoresis. Preliminary results demonstrated that such descriptors have a reasonable ability to differentiate between proteomics patterns that result from exposure to closely related individual chemicals and complex mixtures, such as the jet fuel JP-8. Further research is required to evaluate the utility of these proteomics-based biodescriptors for drug discovery and predictive toxicology.

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Bioinformatics and cheminformatics: Where do the twain meet?

Publication Date: 2008 May PMID: 18428084
Authors: Sukumar, N. - Krein, M. - Breneman, C. M.
Journal: Curr Opin Drug Discov Devel

Bridging the domains of cheminformatics and bioinformatics in the post-genomic era requires the convergence of goals, tools, techniques and annotations. This article reviews recent research at the interface of the domains that shows evidence of this convergence. While graph theoretical representations have long been used to develop simple topological descriptions of molecules, graph theory-based network concepts are also widely employed in systems biology. Shape and conformation are important for understanding intermolecular interactions, and several structure-based cheminformatic descriptors have been developed and applied to drug-like molecules and biomolecules. Data fusion methods and shared ontologies can also help integrate data from multiple sources in order to generate a holistic picture of the shared molecular informatics domain.

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Genomics in drug discovery: The best things come to those who wait.

Publication Date: 2008 May PMID: 18428083
Authors: Bansal, A. T. - Barnes, M. R.
Journal: Curr Opin Drug Discov Devel

The year 2007 has been marked by the maturation of high-throughput technologies that combine automation and miniaturization to enable systematic surveys of genome sequence variation, gene expression and gene function. These technologies have the potential to affect drug discovery in many ways, from target identification and validation, to pinpointing the molecular variants that influence medicine response. In the current climate of declining pharmaceutical R&D productivity, these approaches offer hope, but a price tag is attached. This review covers exciting advances in the field of genomics, and discusses when to act on genomic data versus when to wait for further information.

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Can we help one billion sick people?

Publication Date: 2008 May PMID: 18428082
Authors: Maliski, E. - Gund, P. - Brown, F.
Journal: Curr Opin Drug Discov Devel

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