Meeting report : Neuropathology and Neuropharmacology of Monoaminergic systems

The third EU COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain” Annual Conference entitled “Neuropathology and Neuropharmacology of Monoaminergic Systems” was hosted by the University of Bordeaux, France on 8-10 October 2014. The conference, organized by Prof. De Deurwaerdère, was supported by COST (European Cooperation in Science and Technology) and LABEX (LABEX Brain, University of Bordeaux). The program took the form of a three-day meeting, comprising a series of French and international invited talks and breakout sessions designed to identify key gaps in current knowledge and potential future research questions. The aims of this Conference were two-fold: 1. To identify the current state-of-the-art in the understanding of the pathological mechanisms that contribute to different neuropsychiatric disorders, and to what extent, monoamines a multi-target drugs and/or other interventions might prevent these changes. 2. To identify specific areas of research where information is sparse but which are likely to yield data that will impact on future strategies to treat neurodegenerative disorders.peer-reviewe

MAO and aggression

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Questions in the chemical enzymology of MAO

A.A. is supported by the Slovenian Research Agency (Research Program P1-0005).We have structure, a wealth of kinetic data, thousands of chemical ligands, and clinical 8 information for the effects of a range of drugs on monoamine oxidase activity in vivo. We have 9 comparative information from various species and mutations on kinetics, and effects of inhibition. 10 Yet there are what seem like simple questions still to be answered. This article presents a brief sum-11 mary of existing experimental evidence the background and poses questions that remain intriguing 12 for chemists and biochemists researching the chemical enzymology of and drug design for mono-13 amine oxidases (FAD-containing EC 4.1.3.4).Publisher PDFPeer reviewe

Editorial: Structure-based drug design for diagnosis and treatment of neurological diseases

This editorial and the ebook are based upon collaboration under COST Action CM1103 (NEURODRUG), supported by COST (European Cooperation in Science and Technology).Publisher PDFPeer reviewe

Assessment of enzyme inhibition : a review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs

Both authors are grateful for the collaborations on multi-target drugs facilitated by COST Action CM1103 (2011-2015).The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.Publisher PDFPeer reviewe

Molecular aspects of the activity and inhibition of the FAD-containing monoamine oxidases

1. Introduction 2. FAD: the catalytic cofactor 2.1 FAD is covalently attached to MAO 2.3 FAD is modified by irreversible inhibitors 3. MAO proteins 3.1 MAO protein expression and turnover 3.2 MAO A and MAO B structures and active sites 3.3 MAO chemical mechanism 3.4 MAO kinetic mechanism: two-substrate kinetics 4. Substrate Specificity of these Promiscuous Enzymes 4.1 Neurotransmitter metabolism 4.2 Metabolism of biogenic amines 4.3 Products from MAO catalysis 5. Inhibition of MAO 5.1 Reversible inhibitors of MAO 5.2 Examples of tight binding reversible inhibitors of MAO 5.3 Examples of irreversible inhibitors of MAO 6. Computational innovation 6.1 Theoretical elucidation of mechanism 6.2 Data-mining and tools for drug discovery 7. Conclusion: the future for MAO inhibition in multi-target drugsPostprin

Electron carriers and energy conservation in mitochondrial respiration

The chemical system for the transformation of energy in eukaryotic mitochondria has engaged researchers for almost a century. This summary of four lectures on the electron transport system in mitochondria is an introduction to the mammalian electron transport chain for those unfamiliar with mitochondrial oxidative phosphorylation. It gives references chosen to reflect the history of the field and to highlight some of the recent advances in bioenergetics. The electron transport chain converts the energy that is released as electrons are passed to carriers of progressively higher redox potential into a proton gradient across the membrane that drives adenosine triphosphate (ATP) synthesis. The electron carriers include flavins, iron–sulfur centers, heme groups, and copper to divide the redox change from reduced nicotinamide adenine dinucleotide (NADH) at −320 mV to oxygen at +800 mV into steps that allow conversion and conservation of the energy released in three major complexes (Complexes I, III, and IV) by moving protons across the mitochondrial inner membrane. The three processes of proton pumping are now known after the successful determination of the structures of the large membrane protein complexes involved. Mitochondria and their proteins play roles not only in the production of ATP but also in cell survival, for which energy supply is the key.Publisher PDFPeer reviewe

Neurobiology and neuropharmacology of monoaminergic systems

This Special Issue, and the collaboration among the researchers that contributed to it, was initiated by EU COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”.PostprintPeer reviewe

Updating neuropathology and neuropharmacology of monoaminergic systems

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