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    Targeting serpins in high-throughput and structure-based drug design

    Chang, Y.-P. and Mahadeva, R. and Patschull, A.O.M. and Nobeli, Irene and Ekeowa, U.I. and McKay, A.R. and Thalassinos, Konstantinos and Irving, J.A. and Haq, I. and Nyon, Mun Peak and Christodoulou, John and Ordóñez, A. and Miranda, E. and Gooptu, Bibek (2011) Targeting serpins in high-throughput and structure-based drug design. In: Whisstock, J.C. and Bird, P.I. (eds.) Serpin Structure and Evolution. Methods In Enzymology 501. New York, U.S.: Elsevier, pp. 139-175. ISBN 9780123859501.

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    Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in mechanisms of health (e.g., enzyme inhibition) and disease (serpinopathies). This intrinsic tendency is modifiable by ligand binding, thus structure-based drug design is an attractive strategy in the serpinopathies. This can be viewed as a labor-intensive approach, and historically, its intellectual attractiveness has been tempered by relatively limited success in development of drugs reaching clinical practice. However, the increasing availability of a range of powerful experimental systems and higher-throughput techniques is causing academic and early-stage industrial pharmaceutical approaches to converge. In this review, we outline the different systems and techniques that are bridging the gap between what have traditionally been considered distinct disciplines. The individual methods are not serpin-specific. Indeed, many have only recently been applied to serpins, and thus investigators in other fields may have greater experience of their use to date. However, by presenting examples from our work and that of other investigators in the serpin field, we highlight how techniques with potential for automation and scaling can be combined to address a range of context-specific challenges in targeting the serpinopathies.


    Item Type: Book Section
    Keyword(s) / Subject(s): Serpin, Serpinopathies, Serpin polymerization, Drug development, Orphan diseases, Allosteric targeting, Computational biology, Chemical biology, Structural biology, Cell biology
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Bioinformatics, Bloomsbury Centre for (Closed), Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 24 Jun 2015 14:25
    Last Modified: 02 Aug 2023 17:17


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