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    Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

    Curtin, A.M. and Kinsella, Gemma K. and Stephens, John C. (2015) Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations. Current Medicinal Chemistry, 22 (21). pp. 2558-2579. ISSN 0929-8673

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    Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer’s disease, Parkinson’s disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme - the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

    Item Type: Article
    Additional Information: This is the postprint version of the published article, which is available at doi: 10.2174/0929867322666150429112600
    Keywords: Binding pockets; in silico; neuronal nitric oxide synthase (nNOS); selective inhibition;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7701
    Identification Number:
    Depositing User: Dr John Stephens
    Date Deposited: 10 Jan 2017 15:06
    Journal or Publication Title: Current Medicinal Chemistry
    Publisher: Bentham Science Publishers
    Refereed: Yes
    Funders: Higher Education Authority (HEA), European Regional Development Fund (ERDF)
      Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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