Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.

Animals Binding Sites Carboxylic Ester Hydrolases / antagonists & inhibitors Crystallography, X-Ray Enzyme Inhibitors / chemical synthesis Esterases / antagonists & inhibitors High-Throughput Screening Assays Male Mice Mice, Inbred C57BL Models, Molecular Molecular Docking Simulation Protein Binding Structure-Activity Relationship Wnt Signaling Pathway / drug effects beta Catenin / drug effects

Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
13 01 2022
Historique:
pubmed: 24 12 2021
medline: 8 2 2022
entrez: 23 12 2021
Statut: ppublish

Résumé

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 IC

Identifiants

DOI: 10.1021/acs.jmedchem.1c01735 PMID: 34939789
pubmed: 34939789
doi: 10.1021/acs.jmedchem.1c01735
doi:

Substances chimiques

Enzyme Inhibitors 0
beta Catenin 0
Esterases EC 3.1.-
Carboxylic Ester Hydrolases EC 3.1.1.-
Notum protein, mouse EC 3.1.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

562-578

Subventions

Organisme : Cancer Research UK
ID : C375/A17721
Pays : United Kingdom

Auteurs

David Steadman (D)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
ORCID: 0000-0003-4271-5525

Benjamin N Atkinson (BN)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
ORCID: 0000-0001-5511-9859

Yuguang 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.
ORCID: 0000-0001-8916-8552

Nicky J Willis (NJ)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
ORCID: 0000-0003-3245-5280

Sarah Frew (S)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Amy Monaghan (A)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Chandni Patel (C)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Emma Armstrong (E)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Kathryn Costelloe (K)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Lorenza Magno (L)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

Magda Bictash (M)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.

E Yvonne 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.
ORCID: 0000-0002-3834-1893

Paul V Fish (PV)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
ORCID: 0000-0002-2117-2173

Fredrik Svensson (F)

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, LondonWC1E 6BT, U.K.
ORCID: 0000-0002-5556-8133

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Carboxylic ester hydrolases › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Techniques d'investigation › Tests de criblage à haut débit › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Wnt › Virtual Screening Directly Identifies New...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › bêta-Caténine › Virtual Screening Directly Identifies New...