Petra van der Wouden

University of Groningen, Groningen, Groningen, Netherlands

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Publications (4)15.29 Total impact

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    ABSTRACT: Human 15-lipoxygenase-1 (h-15-LOX-1) is an important mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen containing heterocycles such as indoles, quinolones, pyrazoles etc. We denoted this approach Substitution Oriented fragment Screening (SOS), because it is focuses on identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure activity relationships (SAR) for h-1-5-LOX-1 inhibition. A molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a Ki of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate significant increase of interleukin-10 (IL-10) gene expression, which indicates anti-inflammatory properties.
    Journal of Medicinal Chemistry 09/2015; DOI:10.1021/acs.jmedchem.5b01121 · 5.45 Impact Factor
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    ABSTRACT: Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15-LOX-1) is an important mammalian lipoxygenase and plays a crucial regulatory role in several respiratory diseases such as asthma, COPD and chronic bronchitis. Novel potent and selective inhibitors of 15-LOX-1 are required to explore the role of this enzyme in drug discovery. In this study we describe structure activity relationships for 6-benzyloxysalicylates as inhibitors of human 15-LOX-1. Kinetic analysis suggests competitive inhibition and the binding model of these compounds can be rationalized using molecular modelling studies. The most potent derivative 37a shows a Ki value of 1.7 μM. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 04/2015; 94. DOI:10.1016/j.ejmech.2015.03.007 · 3.45 Impact Factor
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    ABSTRACT: In a forward genetic screen in Drosophila melanogaster, aimed to identify genes required for normal locomotor function, we isolated dPPCS (the second enzyme of the Coenzyme A biosynthesis pathway). The entire Drosophila CoA synthesis route was dissected, annotated and additional CoA mutants were obtained (dPANK/fumble) or generated (dPPAT-DPCK). Drosophila CoA mutants suffer from neurodegeneration, altered lipid homeostasis and the larval brains display increased apoptosis. Also, de novo CoA biosynthesis is required to maintain DNA integrity during the development of the central nervous system. In humans, mutations in the PANK2 gene, the first enzyme in the CoA synthesis route, are associated with pantothenate kinase-associated neurodegeneration. Currently, the pathogenesis of this neurodegenerative disease is poorly understood. We provide the first comprehensive analysis of the physiological implications of mutations in the entire CoA biosynthesis route in an animal model system. Surprisingly, our findings reveal a major role of this conserved pathway in maintaining DNA and cellular integrity, explaining how impaired CoA synthesis during CNS development can elicit a neurodegenerative phenotype.
    Human Molecular Genetics 08/2008; 17(13):2058-69. DOI:10.1093/hmg/ddn105 · 6.39 Impact Factor
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