Exploring protein hotspots by optimized fragment pharmacophores.

Animals Cell Survival Chlorocebus aethiops Computational Chemistry Coronavirus 3C Proteases / chemistry Coronavirus Papain-Like Proteases / chemistry Crystallography, X-Ray Databases, Protein Drug Design Drug Development / methods Drug Discovery / methods HEK293 Cells High-Throughput Screening Assays / methods Histone-Lysine N-Methyltransferase / chemistry Humans Hydrogen Bonding Hydrophobic and Hydrophilic Interactions Ligands Protein Binding Receptors, G-Protein-Coupled / chemistry SARS-CoV-2 / chemistry Small Molecule Libraries Vero Cells

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
27 05 2021
Historique:
received: 06 11 2020
accepted: 29 04 2021
entrez: 28 5 2021
pubmed: 29 5 2021
medline: 11 6 2021
Statut: epublish

Résumé

Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2.

Identifiants

DOI: 10.1038/s41467-021-23443-y PMID: 34045440 PMC: PMC8159961
pubmed: 34045440
doi: 10.1038/s41467-021-23443-y
pii: 10.1038/s41467-021-23443-y
pmc: PMC8159961
doi:

Substances chimiques

Ligands 0
Receptors, G-Protein-Coupled 0
Small Molecule Libraries 0
Histone-Lysine N-Methyltransferase EC 2.1.1.43
SETD2 protein, human EC 2.1.1.43
Coronavirus Papain-Like Proteases EC 3.4.22.2
papain-like protease, SARS-CoV-2 EC 3.4.22.2
Coronavirus 3C Proteases EC 3.4.22.28

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

3201

Subventions

Organisme : NIGMS NIH HHS
ID : R35 GM118078
Pays : United States

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Auteurs

Dávid Bajusz (D)

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary.
ORCID: 0000-0003-4277-9481

Warren S Wade (WS)

BioBlocks, Inc., San Diego, CA, USA.

Grzegorz Satała (G)

Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland.

Andrzej J Bojarski (AJ)

Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland.

Janez Ilaš (J)

Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
ORCID: 0000-0002-0124-0474

Jessica Ebner (J)

Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.

Florian Grebien (F)

Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.
ORCID: 0000-0003-4289-2281

Henrietta Papp (H)

National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
ORCID: 0000-0003-3887-5657

Ferenc Jakab (F)

National Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary.

Alice Douangamath (A)

Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK.
ORCID: 0000-0002-9196-8644

Daren Fearon (D)

Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK.
ORCID: 0000-0003-3529-7863

Frank von Delft (F)

Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, UK.
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK.
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK.
Centre for Medicines Discovery, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK.
Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa.
ORCID: 0000-0003-0378-0017

Marion Schuller (M)

Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

Ivan Ahel (I)

Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

Amanda Wakefield (A)

Department of Chemistry, Boston University, Boston, MA, USA.
Department of Biomedical Engineering, Boston University, Boston, MA, USA.

Sándor Vajda (S)

Department of Chemistry, Boston University, Boston, MA, USA.
Department of Biomedical Engineering, Boston University, Boston, MA, USA.

János Gerencsér (J)

BioBlocks, Inc., San Diego, CA, USA.
ORCID: 0000-0002-1928-0650

Péter Pallai (P)

BioBlocks, Inc., San Diego, CA, USA.

György M Keserű (GM)

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary. keseru.gyorgy@ttk.hu.
ORCID: 0000-0003-1039-7809

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Exploring protein hotspots by optimized...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › Exploring protein hotspots by optimized...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Cercopithecus › Cercopithecus aethiops › Exploring protein hotspots by optimized...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Chimie computationnelle › Exploring protein hotspots by optimized...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales non structurales › Protéases virales › Protéases virales 3C › Protéases 3C des coronavirus › Exploring protein hotspots by optimized...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales non structurales › Protéases virales › Protéases virales de type papaïne › Protéases de type papaïne des coronavirus › Exploring protein hotspots by optimized...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Exploring protein hotspots by optimized...
questionsmedicales.fr › Sciences de l'information › Mémorisation et recherche des informations › Bases de données comme sujet › Bases de données factuelles › Bases de données génétiques › Bases de données de protéines › Exploring protein hotspots by optimized...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Exploring protein hotspots by optimized...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Exploring protein hotspots by optimized...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Exploring protein hotspots by optimized...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Exploring protein hotspots by optimized...
questionsmedicales.fr › Techniques d'investigation › Tests de criblage à haut débit › Exploring protein hotspots by optimized...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Histone méthyltransférases › Histone-lysine N-methyltransferase › Exploring protein hotspots by optimized...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Exploring protein hotspots by optimized...
questionsmedicales.fr › Phénomènes chimiques › Liaison hydrogène › Exploring protein hotspots by optimized...
questionsmedicales.fr › Phénomènes chimiques › Interactions hydrophobes et hydrophiles › Exploring protein hotspots by optimized...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Ligands › Exploring protein hotspots by optimized...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Exploring protein hotspots by optimized...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Exploring protein hotspots by optimized...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Exploring protein hotspots by optimized...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › Exploring protein hotspots by optimized...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules Vero › Exploring protein hotspots by optimized...