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      A ‘rule of 0.5’ for the metabolite-likeness of approved pharmaceutical drugs

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          Abstract

          We exploit the recent availability of a community reconstruction of the human metabolic network (‘Recon2’) to study how close in structural terms are marketed drugs to the nearest known metabolite(s) that Recon2 contains. While other encodings using different kinds of chemical fingerprints give greater differences, we find using the 166 Public MDL Molecular Access (MACCS) keys that 90 % of marketed drugs have a Tanimoto similarity of more than 0.5 to the (structurally) ‘nearest’ human metabolite. This suggests a ‘rule of 0.5’ mnemonic for assessing the metabolite-like properties that characterise successful, marketed drugs. Multiobjective clustering leads to a similar conclusion, while artificial (synthetic) structures are seen to be less human-metabolite-like. This ‘rule of 0.5’ may have considerable predictive value in chemical biology and drug discovery, and may represent a powerful filter for decision making processes.

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          The online version of this article (doi:10.1007/s11306-014-0733-z) contains supplementary material, which is available to authorized users.

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          Membrane transporters in drug development.

          Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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            MetaboLights—an open-access general-purpose repository for metabolomics studies and associated meta-data

            MetaboLights (http://www.ebi.ac.uk/metabolights) is the first general-purpose, open-access repository for metabolomics studies, their raw experimental data and associated metadata, maintained by one of the major open-access data providers in molecular biology. Metabolomic profiling is an important tool for research into biological functioning and into the systemic perturbations caused by diseases, diet and the environment. The effectiveness of such methods depends on the availability of public open data across a broad range of experimental methods and conditions. The MetaboLights repository, powered by the open source ISA framework, is cross-species and cross-technique. It will cover metabolite structures and their reference spectra as well as their biological roles, locations, concentrations and raw data from metabolic experiments. Studies automatically receive a stable unique accession number that can be used as a publication reference (e.g. MTBLS1). At present, the repository includes 15 submitted studies, encompassing 93 protocols for 714 assays, and span over 8 different species including human, Caenorhabditis elegans, Mus musculus and Arabidopsis thaliana. Eight hundred twenty-seven of the metabolites identified in these studies have been mapped to ChEBI. These studies cover a variety of techniques, including NMR spectroscopy and mass spectrometry.
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              The Chemistry Development Kit (CDK): An Open-Source Java Library for Chemo-and Bioinformatics

              The Chemistry Development Kit (CDK) is a freely available open-source Java library for Structural Chemo-and Bioinformatics. Its architecture and capabilities as well as the development as an open-source project by a team of international collaborators from academic and industrial institutions is described. The CDK provides methods for many common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc. Application scenarios as well as access information for interested users and potential contributors are given.
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                Author and article information

                Contributors
                +44 161 306 4492 , dbk@manchester.ac.uk , http://dbkgroup.org/
                Journal
                Metabolomics
                Metabolomics
                Metabolomics
                Springer US (Boston )
                1573-3882
                1573-3890
                19 September 2014
                19 September 2014
                2015
                : 11
                : 2
                : 323-339
                Affiliations
                [ ]School of Chemistry, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK
                [ ]The Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK
                [ ]School of Computer Science, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK
                [ ]Manchester Business School, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK
                Article
                733
                10.1007/s11306-014-0733-z
                4342520
                25750602
                813c19c7-9dde-4da7-a96c-b4c891adf606
                © The Author(s) 2014

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 4 July 2014
                : 8 September 2014
                Categories
                Original Article
                Custom metadata
                © Springer Science+Business Media New York 2015

                Molecular biology
                genome-wide metabolic reconstruction,recon 2,cheminformatics,knime,metabolite-likeness,drug-likeness

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