Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions

Autor: Marie-Edith Gourdel, Christophe Muller, Stéphane Bourg, Philippe Roche, Carine Derviaux, Olivier Sperandio, Bruno O. Villoutreix, David Lagorce, Xavier Morelli, Maria A. Miteva, Jean-Christophe Rain, Laurent Hoffer, Thomas W. Miller, Pascal Bonnet, Nicolas Bosc
Přispěvatelé: Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hybrigenics [Paris], Hybrigenics, Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), This work was supported by research funding from the French National Research Agency (ANR-15-CE18-0023, ANR-18-CE11-0023 and ANR-20-COVI-0047), Canceropole PACA Prematuration and U01 CA218259/CA/NCI NIH HHS (USA). N.B. and L.H. were supported by fellowships from ANR-15-CE18-0023. S.B. and P.B. wish to thank the Région Centre Val de Loire for financial support., We acknowledge the Datacentre IT and Scientific Computing plateform of the CRCM., ANR-15-CE18-0023,PPI-Chem,Développement de stratégies innovantes ciblant la modulation spécifique de complexes protéine-proteine(2015), ANR-18-CE11-0023,T6MeD-OC,DE LA DYNAMIQUE ET DIVERSITÉ STRUCTURALE DES COMPLEXES MEMBRANES DU T6SS VERS LE DÉVELOPPEMENT D'INHIBITEUR DE LA VIRULENCE(2018), Bioinformatique structurale, Institut des Matériaux, de Microélectronique et des Nanosciences de Provence (IM2NP), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bidaut, Ghislain, Développement de stratégies innovantes ciblant la modulation spécifique de complexes protéine-proteine - - PPI-Chem2015 - ANR-15-CE18-0023 - AAPG2015 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - DE LA DYNAMIQUE ET DIVERSITÉ STRUCTURALE DES COMPLEXES MEMBRANES DU T6SS VERS LE DÉVELOPPEMENT D'INHIBITEUR DE LA VIRULENCE - - T6MeD-OC2018 - ANR-18-CE11-0023 - AAPG2018 - VALID
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Computer science
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
01 natural sciences
Biochemistry
drugs
Chemical library
protein-protein interaction
chemistry.chemical_compound
Drug Discovery
inhibitors
[CHIM.CHEM] Chemical Sciences/Cheminformatics
Protein Interaction Maps
CD47
ComputingMilieux_MISCELLANEOUS
[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
QSAR
General Medicine
[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Diversity Library
Molecular Medicine
HTS
[CHIM.CHEM]Chemical Sciences/Cheminformatics
Quantitative structure–activity relationship
PPI
[CHIM.THER] Chemical Sciences/Medicinal Chemistry
Chemical biology
chemical biology
Computational biology
focused library
Article
Protein–protein interaction
diversity
Small Molecule Libraries
03 medical and health sciences
Molecular descriptor
On demand
SIRPα
Cluster analysis
010405 organic chemistry
screening
Reproducibility of Results
High-Throughput Screening Assays
0104 chemical sciences
030104 developmental biology
ADMET
Models
Chemical
chemistry
chemical libraries
Databases
Chemical
Zdroj: ACS Chemical Biology
ACS Chemical Biology, American Chemical Society, 2020, 15 (6), pp.1566-1574. ⟨10.1021/acschembio.0c00179⟩
ACS Chemical Biology, 2020, 15 (6), pp.1566-1574. ⟨10.1021/acschembio.0c00179⟩
ACS Chem Biol
ISSN: 1554-8929
1554-8937
DOI: 10.1021/acschembio.0c00179⟩
Popis: International audience; Protein-protein interactions (PPIs) mediate nearly every cellular process and represent attractive targets for modulating disease states but are challenging to target with small molecules. Despite this, several PPI inhibitors (iPPIs) have entered clinical trials, and a growing number of PPIs have become validated drug targets. However, high-throughput screening efforts still endure low hit rates mainly because of the use of unsuitable screening libraries. Here, we describe the collective effort of a French consortium to build, select, and store in plates a unique chemical library dedicated to the inhibition of PPIs. Using two independent predictive models and two updated databases of experimentally confirmed PPI inhibitors developed by members of the consortium, we built models based on different training sets, molecular descriptors, and machine learning methods. Independent statistical models were used to select putative PPI inhibitors from large commercial compound collections showing great complementarity. Medicinal chemistry filters were applied to remove undesirable structures from this set (such as PAINS, frequent hitters, and toxic compounds) and to improve drug likeness. The remaining compounds were subjected to a clustering procedure to reduce the final size of the library while maintaining its chemical diversity. In practice, the library showed a 46-fold activity rate enhancement when compared to a non-iPPI-enriched diversity library in high-throughput screening against the CD47-SIRPα PPI. The Fr-PPIChem library is plated in 384-well plates and will be distributed on demand to the scientific community as a powerful tool for discovering new chemical probes and early hits for the development of potential therapeutic drugs.
Databáze: OpenAIRE
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