DDTEC-427; No of Pages 2
Drug Discovery Today: Technologies
Vol. xxx, No. xx 2015
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Editorial Pascal de Tullio Center for Interdisciplinary Research on Medicines (CIRM), University of Lie`ge, Belgium. Email: ([email protected])
Before starting this editorial dedicated to metabolomics in the drug discovery process, it is worth clarifying the semantic debate between scientists that use metabolomics terminology and others that prefers metabonomics. Without entering into definitions and complex explanations that will be discussed by some authors of this issue, we can just mention that both words have been used since the first publications in this field to represent the same approach. However, for several years, metabolomics has become the term currently more employed, even if metabonomics remains popular in the toxicological applications. Therefore, even if we have chosen to join the ‘majority’ for the presentation of this issue, other authors remain free to use both terms in their reviews. After several years of technical and methodological development, metabolomics (MBX) is now a well-accepted and validated approach, and interest in it is growing in many scientific areas. MBX is generally defined as the qualitative and quantitative study of the small molecular weight molecules (metabolites) present in a biological system. Among all the metabolites, lipids are considered to be an essential and crucial class of compound and have given rise to a metabolomics subcategory named lipidomics. This approach is expected to complete the information coming from the genomics, transcriptomics and proteomics level by exploring the end points of the complex biological systems. It provides a unique and holistic snapshot of the global state of a cell, organ or organism at a certain time point, but could also follow the dynamic responses to external or internal stimuli. Genomics leads to a major but ‘static’ analysis of a living organism while proteomic and transcriptomic information seem to be difficult to correlate with biological functions. By an evaluation of the changes at the last organizational level, metabolomics could be able to better understand the correlations between a cell state and its environment conditions. This approach provides unique, challenging opportunities to link dynamic variations of the metabolome with a physiological or a pathological status and offers an innovative global insight into the relationships
1740-6749/$ ß 2015 Elsevier Ltd. All rights reserved.
between genes, gene expression, environment, phenotype, lifestyle and pathologies. MBX could be considered the ‘missing link’ between genetic pre-disposition, transcription functions and external parameters such as lifestyle, pathologies, toxicity and external stimuli such as drugs. The comprehension of the mechanisms that underlie the transition from a physiological state to a pathophysiological state and the converse is of great interest for the discovery and the development of therapeutic strategies. Then, next to the classical applications of MBX such as quality control in food, nutrition and plants, functional genomics studies, taxonomy, biomarkers finding, diagnosis, toxicity studies, epidemiology, comprehension of biological system, diseases insights, etc., metabolomics is expected to become an important tool in the drug discovery process. Indeed, the rapid identification and validation of new targets, dynamic studies of the physiological response to drugs in pre-clinical and clinical approaches and the evaluation of drug candidate toxicity are the most challenging features that have to be reached to develop new drugs and new treatments. MBX is particularly adapted to easily monitor the effects of drugs on the metabolome, in pathological and physiological conditions, to identify putative toxic effects of a lead compound, to highlight the biochemical pathways or proteins targeted
Pascal de Tullio, pHD, is Senior Research Associate from the Fond National de la Recherche Scientifique (FNRS) and Member of the Center for Interdisciplinary Research on Medicines (CIRM) from the University of Lie`ge. He is working in the Department of Medicinal Chemistry where he is responsible of the NMR and metabolomics unit. He is implicated from several years in the development and the promotion of metabolomics in Belgium and is currently president of the FNRS contact group in metabolomics.
http://dx.doi.org/10.1016/j.ddtec.2015.01.001
Please cite this article in press as: Drug Discov Today: Technol (2015), http://dx.doi.org/10.1016/j.ddtec.2015.01.001
e1
DDTEC-427; No of Pages 2 Drug Discovery Today: Technologies |
by a drug. Indeed, it is expected that in in vitro and in vivo preclinical models as well as in clinical studies, drugs, drug candidates or hit to lead compounds impact the metabolic profile of the cells or organism. The observation of these dynamic changes could lead to key information concerning the positive as well as the negatives effects of the compounds on the studied biological systems. This could greatly help the evaluation of a drug candidate’s efficacy, safety and the validation of the target in its development process. Different approaches are included into the term metabolomics. A distinction could indeed be made between pattern or fingerprint analysis, targeted or biology-driven MBX and nontargeted MBX. Non-targeted MBX is defined as the extensive and comprehensive analysis of the larger number of analytes in a sample without a selection based on the chemical classes or the biological activities. Targeted metabolomics could be seen as the measurement of identified, chemically similar metabolites or groups of biochemically annotated metabolites. Pattern or fingerprint analysis, known also as metabolomic fingerprinting, identifies or correlates a global metabolic snapshot with a physiological or pathological state of an organism without identifying the metabolites. These different approaches are currently used in the drug discovery processes. For a long time, the major challenge of a metabolomics analysis has been the capability of the analytical methods and techniques to visualize, identify and quantify the greatest part of the existing metabolome. This issue has been assessed through the major and recent technological developments of Mass Spectrometry (MS) and Nuclear Magnetic Resonance
e2
Vol. xxx, No. xx 2015
(NMR). These two platforms, combined or not with separative methods (gas chromatography (GC), liquid chromatography (LC) or capillary electrophoresis (CE)) and the improvement of the automation procedures have greatly increased the potency and the usefulness of metabolomics in different research areas and especially in the pharmaceutical domain. Molecular imaging MBX represents an innovative and new application that could be integrated in the near future with more classical approaches. Finally, to analyze and generate useful data, MBX studies have required the development of powerful processing, chemometric and statistical tools. Even though methodological developments are still required, MBX has now reached sufficient maturity to be integrated into the tools useful for target discovery and validation and rational drug discovery, design and development. Moreover, natural products have been in the past a great source of drugs and still represent a large reserve for new putative drugs with a high chemical originality and diversity. MBX applied to natural products also represents a major and challenging area with huge possibility for development. This issue will provide an overview of the applications and potentialities of MBX in the drug discovery process, staring from a general overview and going into a presentation of the analytical tools and of some applications in plant metabolomics and lipidomics. With best wishes, Pascal de Tullio
www.drugdiscoverytoday.com
Please cite this article in press as: Drug Discov Today: Technol (2015), http://dx.doi.org/10.1016/j.ddtec.2015.01.001
Drug Discovery Today: Technologies
Vol. xxx, No. xx 2015
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Editorial Pascal de Tullio Center for Interdisciplinary Research on Medicines (CIRM), University of Lie`ge, Belgium. Email: ([email protected])
Before starting this editorial dedicated to metabolomics in the drug discovery process, it is worth clarifying the semantic debate between scientists that use metabolomics terminology and others that prefers metabonomics. Without entering into definitions and complex explanations that will be discussed by some authors of this issue, we can just mention that both words have been used since the first publications in this field to represent the same approach. However, for several years, metabolomics has become the term currently more employed, even if metabonomics remains popular in the toxicological applications. Therefore, even if we have chosen to join the ‘majority’ for the presentation of this issue, other authors remain free to use both terms in their reviews. After several years of technical and methodological development, metabolomics (MBX) is now a well-accepted and validated approach, and interest in it is growing in many scientific areas. MBX is generally defined as the qualitative and quantitative study of the small molecular weight molecules (metabolites) present in a biological system. Among all the metabolites, lipids are considered to be an essential and crucial class of compound and have given rise to a metabolomics subcategory named lipidomics. This approach is expected to complete the information coming from the genomics, transcriptomics and proteomics level by exploring the end points of the complex biological systems. It provides a unique and holistic snapshot of the global state of a cell, organ or organism at a certain time point, but could also follow the dynamic responses to external or internal stimuli. Genomics leads to a major but ‘static’ analysis of a living organism while proteomic and transcriptomic information seem to be difficult to correlate with biological functions. By an evaluation of the changes at the last organizational level, metabolomics could be able to better understand the correlations between a cell state and its environment conditions. This approach provides unique, challenging opportunities to link dynamic variations of the metabolome with a physiological or a pathological status and offers an innovative global insight into the relationships
1740-6749/$ ß 2015 Elsevier Ltd. All rights reserved.
between genes, gene expression, environment, phenotype, lifestyle and pathologies. MBX could be considered the ‘missing link’ between genetic pre-disposition, transcription functions and external parameters such as lifestyle, pathologies, toxicity and external stimuli such as drugs. The comprehension of the mechanisms that underlie the transition from a physiological state to a pathophysiological state and the converse is of great interest for the discovery and the development of therapeutic strategies. Then, next to the classical applications of MBX such as quality control in food, nutrition and plants, functional genomics studies, taxonomy, biomarkers finding, diagnosis, toxicity studies, epidemiology, comprehension of biological system, diseases insights, etc., metabolomics is expected to become an important tool in the drug discovery process. Indeed, the rapid identification and validation of new targets, dynamic studies of the physiological response to drugs in pre-clinical and clinical approaches and the evaluation of drug candidate toxicity are the most challenging features that have to be reached to develop new drugs and new treatments. MBX is particularly adapted to easily monitor the effects of drugs on the metabolome, in pathological and physiological conditions, to identify putative toxic effects of a lead compound, to highlight the biochemical pathways or proteins targeted
Pascal de Tullio, pHD, is Senior Research Associate from the Fond National de la Recherche Scientifique (FNRS) and Member of the Center for Interdisciplinary Research on Medicines (CIRM) from the University of Lie`ge. He is working in the Department of Medicinal Chemistry where he is responsible of the NMR and metabolomics unit. He is implicated from several years in the development and the promotion of metabolomics in Belgium and is currently president of the FNRS contact group in metabolomics.
http://dx.doi.org/10.1016/j.ddtec.2015.01.001
Please cite this article in press as: Drug Discov Today: Technol (2015), http://dx.doi.org/10.1016/j.ddtec.2015.01.001
e1
DDTEC-427; No of Pages 2 Drug Discovery Today: Technologies |
by a drug. Indeed, it is expected that in in vitro and in vivo preclinical models as well as in clinical studies, drugs, drug candidates or hit to lead compounds impact the metabolic profile of the cells or organism. The observation of these dynamic changes could lead to key information concerning the positive as well as the negatives effects of the compounds on the studied biological systems. This could greatly help the evaluation of a drug candidate’s efficacy, safety and the validation of the target in its development process. Different approaches are included into the term metabolomics. A distinction could indeed be made between pattern or fingerprint analysis, targeted or biology-driven MBX and nontargeted MBX. Non-targeted MBX is defined as the extensive and comprehensive analysis of the larger number of analytes in a sample without a selection based on the chemical classes or the biological activities. Targeted metabolomics could be seen as the measurement of identified, chemically similar metabolites or groups of biochemically annotated metabolites. Pattern or fingerprint analysis, known also as metabolomic fingerprinting, identifies or correlates a global metabolic snapshot with a physiological or pathological state of an organism without identifying the metabolites. These different approaches are currently used in the drug discovery processes. For a long time, the major challenge of a metabolomics analysis has been the capability of the analytical methods and techniques to visualize, identify and quantify the greatest part of the existing metabolome. This issue has been assessed through the major and recent technological developments of Mass Spectrometry (MS) and Nuclear Magnetic Resonance
e2
Vol. xxx, No. xx 2015
(NMR). These two platforms, combined or not with separative methods (gas chromatography (GC), liquid chromatography (LC) or capillary electrophoresis (CE)) and the improvement of the automation procedures have greatly increased the potency and the usefulness of metabolomics in different research areas and especially in the pharmaceutical domain. Molecular imaging MBX represents an innovative and new application that could be integrated in the near future with more classical approaches. Finally, to analyze and generate useful data, MBX studies have required the development of powerful processing, chemometric and statistical tools. Even though methodological developments are still required, MBX has now reached sufficient maturity to be integrated into the tools useful for target discovery and validation and rational drug discovery, design and development. Moreover, natural products have been in the past a great source of drugs and still represent a large reserve for new putative drugs with a high chemical originality and diversity. MBX applied to natural products also represents a major and challenging area with huge possibility for development. This issue will provide an overview of the applications and potentialities of MBX in the drug discovery process, staring from a general overview and going into a presentation of the analytical tools and of some applications in plant metabolomics and lipidomics. With best wishes, Pascal de Tullio
www.drugdiscoverytoday.com
Please cite this article in press as: Drug Discov Today: Technol (2015), http://dx.doi.org/10.1016/j.ddtec.2015.01.001
