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Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
Steadman, David; Atkinson, Benjamin N; Zhao, Yuguang; Willis, Nicky J; Frew, Sarah; Monaghan, Amy; Patel, Chandni; Armstrong, Emma; Costelloe, Kathryn; Magno, Lorenza; Bictash, Magda; Jones, E Yvonne; Fish, Paul V; Svensson, Fredrik.
Afiliación
  • Steadman D; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Atkinson BN; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Zhao Y; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, OxfordOX3 7BN, U.K.
  • Willis NJ; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Frew S; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Monaghan A; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Patel C; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Armstrong E; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Costelloe K; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Magno L; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Bictash M; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Jones EY; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, OxfordOX3 7BN, U.K.
  • Fish PV; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
  • Svensson F; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
J Med Chem ; 65(1): 562-578, 2022 01 13.
Article en En | MEDLINE | ID: mdl-34939789
Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/ß-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hidrolasas de Éster Carboxílico / Inhibidores Enzimáticos / Esterasas Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hidrolasas de Éster Carboxílico / Inhibidores Enzimáticos / Esterasas Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos