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      The Current State of Drug Discovery and a Potential Role for NMR Metabolomics : Miniperspective

      review-article
      Journal of Medicinal Chemistry
      American Chemical Society

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          Abstract

          The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on high-throughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics.

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          Most cited references50

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          Metabolomics--the link between genotypes and phenotypes.

          Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms 'transcriptome' and proteome', the set of metabolites synthesized by a biological system constitute its 'metabolome'. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.
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            Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy.

            The study of biological systems in a holistic manner (systems biology) is increasingly being viewed as a necessity to provide qualitative and quantitative descriptions of the emergent properties of the complete system. Systems biology performs studies focussed on the complex interactions of system components; emphasising the whole system rather than the individual parts. Many perturbations to mammalian systems (diet, disease, drugs) are multi-factorial and the study of small parts of the system is insufficient to understand the complete phenotypic changes induced. Metabolomics is one functional level tool being employed to investigate the complex interactions of metabolites with other metabolites (metabolism) but also the regulatory role metabolites provide through interaction with genes, transcripts and proteins (e.g. allosteric regulation). Technological developments are the driving force behind advances in scientific knowledge. Recent advances in the two analytical platforms of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have driven forward the discipline of metabolomics. In this critical review, an introduction to metabolites, metabolomes, metabolomics and the role of MS and NMR spectroscopy will be provided. The applications of metabolomics in mammalian systems biology for the study of the health-disease continuum, drug efficacy and toxicity and dietary effects on mammalian health will be reviewed. The current limitations and future goals of metabolomics in systems biology will also be discussed (374 references).
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              Statistical practice in high-throughput screening data analysis.

              High-throughput screening is an early critical step in drug discovery. Its aim is to screen a large number of diverse chemical compounds to identify candidate 'hits' rapidly and accurately. Few statistical tools are currently available, however, to detect quality hits with a high degree of confidence. We examine statistical aspects of data preprocessing and hit identification for primary screens. We focus on concerns related to positional effects of wells within plates, choice of hit threshold and the importance of minimizing false-positive and false-negative rates. We argue that replicate measurements are needed to verify assumptions of current methods and to suggest data analysis strategies when assumptions are not met. The integration of replicates with robust statistical methods in primary screens will facilitate the discovery of reliable hits, ultimately improving the sensitivity and specificity of the screening process.
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                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                19 February 2015
                19 February 2014
                24 July 2014
                : 57
                : 14
                : 5860-5870
                Affiliations
                [1]Department of Chemistry, University of Nebraska—Lincoln , 722 Hamilton Hall, Lincoln, Nebraska 68588-0304, United States
                Author notes
                [* ]Phone: 402-472-3039. Fax: 402-472-9402. E-mail: rpowers3@ 123456unl.edu .
                Article
                10.1021/jm401803b
                4324437
                24588729
                42f46a4b-eaa6-425b-91b9-f24ebd642c73
                Copyright © 2014 American Chemical Society

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                : 21 November 2013
                Funding
                National Institutes of Health, United States
                Categories
                Perspective
                Custom metadata
                jm401803b
                jm-2013-01803b

                Pharmaceutical chemistry
                Pharmaceutical chemistry

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