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  1. Article ; Online: Big data and benchmarking initiatives to bridge the gap from AlphaFold to drug design.

    Schapira, Matthieu / Halabelian, Levon / Arrowsmith, Cheryl H / Harding, Rachel J

    Nature chemical biology

    2024  

    Language English
    Publishing date 2024-03-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-024-01570-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
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  2. Article ; Online: Emerging structure-based computational methods to screen the exploding accessible chemical space.

    Bedart, Corentin / Simoben, Conrad Veranso / Schapira, Matthieu

    Current opinion in structural biology

    2024  Volume 86, Page(s) 102812

    Abstract: Structure-based virtual screening can be a valuable approach to computationally select hit candidates based on their predicted interaction with a protein of interest. The recent explosion in the size of chemical libraries increases the chances of hitting ...

    Abstract Structure-based virtual screening can be a valuable approach to computationally select hit candidates based on their predicted interaction with a protein of interest. The recent explosion in the size of chemical libraries increases the chances of hitting high-quality compounds during virtual screening exercises but also poses new challenges as the number of chemically accessible molecules grows faster than the computing power necessary to screen them. We review here two novel approaches rapidly gaining in popularity to address this problem: machine learning-accelerated and synthon-based library screening. We summarize the results from seminal proof-of-concept studies, highlight the latest developments, and discuss limitations and future directions.
    Language English
    Publishing date 2024-04-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2024.102812
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3206: Show issues Location:
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  3. Article ; Online: Methods for computer-assisted PROTAC design.

    Rovers, Evianne / Schapira, Matthieu

    Methods in enzymology

    2023  Volume 690, Page(s) 311–340

    Abstract: Proximity-induced pharmacology is an emerging field in chemical biology and drug discovery where a small molecule induces non-natural interactions between two proteins, leading to specific phenotypic responses. Proteolysis targeting chimeras (PROTACs) ... ...

    Abstract Proximity-induced pharmacology is an emerging field in chemical biology and drug discovery where a small molecule induces non-natural interactions between two proteins, leading to specific phenotypic responses. Proteolysis targeting chimeras (PROTACs) are the most mature examples, where ligands for an E3 ligase and a target protein are linked to induce the ubiquitination and subsequent degradation of the target. The discovery of PROTACs typically relies on a trial-and-error approach where chemical handles and linker chemistry, length and attachment points are systematically varied in the hope that one of the combinations will produce an active molecule. Novel computational methods and tools are developed in an attempt to rationalize and accelerate this process and differ significantly from traditional structure-based drug design approaches. In this chapter, we review three different solutions for computer-assisted PROTAC design: MOE, ICM and PRosettaC. Specifically, we describe protocols to predict the structure of ternary complexes (E3 ligase-PROTAC-target protein) and to screen virtually libraries of PROTAC candidates. We also provide troubleshooting tips. Rational PROTAC design is still in its infancy. By opening this space to users and developers, we hope that this methods article will contribute to much needed advancement in the field.
    MeSH term(s) Proteolysis ; Ubiquitin-Protein Ligases/metabolism ; Proteins/metabolism ; Ubiquitination ; Computers
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteins
    Language English
    Publishing date 2023-07-21
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1557-7988
    ISSN (online) 1557-7988
    DOI 10.1016/bs.mie.2023.06.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The Promise and Peril of Chemical Probe Negative Controls.

    Lee, Jinyoung / Schapira, Matthieu

    ACS chemical biology

    2021  Volume 16, Issue 4, Page(s) 579–585

    Abstract: Chemical probes are selective modulators that are used in cell assays to link a phenotype to a gene and have become indispensable tools to explore gene function and discover therapeutic targets. Chemical probe off-targets are a confounding factor as the ... ...

    Abstract Chemical probes are selective modulators that are used in cell assays to link a phenotype to a gene and have become indispensable tools to explore gene function and discover therapeutic targets. Chemical probe off-targets are a confounding factor as the observed phenotype may be driven by inhibition of an unknown off-target instead of the targeted protein. A negative control, a close chemical analog of the chemical probe that is inactive against the intended target, is typically used to verify that the phenotype is indeed driven by the targeted protein. Here, we compare the selectivity profiles of four unrelated chemical probes and their respective negative controls. We find that controls that chemically deviate from the probe by a single heavy atom can be inactive against up to 80% of known off-targets if the chemical modification has a charge-neutralizing effect. In such cases, a loss in phenotype upon treatment with the negative control may be driven by loss of inhibition of an off-target. To expand this analysis, we inspect the crystal structures of 90 pairs of unrelated proteins, where both proteins within each pair is in complex with the same drug-like ligand. We computationally estimate that in 50% of cases, methylation of the ligand (a simple chemical modification often used to generate negative controls) at a position that will preclude binding to one protein (the intended target) will also preclude binding to the other (the off-target). These results emphasize the need to select negative controls with care and profile both chemical probes and negative controls against diverse protein arrays to verify that off-targets of probes are also hit by negative controls. When available, a best practice should be to verify that two unrelated chemical probes targeting the same protein elicit the same phenotype.
    MeSH term(s) Databases, Protein ; Humans ; Ligands ; Molecular Probes/chemistry ; Small Molecule Libraries/chemistry
    Chemical Substances Ligands ; Molecular Probes ; Small Molecule Libraries
    Language English
    Publishing date 2021-03-21
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.1c00036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Chemical Inhibition of Protein Methyltransferases.

    Schapira, Matthieu

    Cell chemical biology

    2016  Volume 23, Issue 9, Page(s) 1067–1076

    Abstract: Protein methyltransferases (PMTs) participate in the epigenetic control of cell fate and other signaling pathways that are deregulated in disease, and the first PMT inhibitors have entered clinical trials in oncology. This review discusses structural ... ...

    Abstract Protein methyltransferases (PMTs) participate in the epigenetic control of cell fate and other signaling pathways that are deregulated in disease, and the first PMT inhibitors have entered clinical trials in oncology. This review discusses structural studies that recently uncovered the mode of action of compounds in the clinic, as well as challenges and opportunities in the development of PMT inhibitors. It examines inhibitors that compete with the highly polar cofactor but preserve cell penetrance, and allosteric modes of inhibition. Vectors of optimization at the substrate-binding site and the potential of fragment screening approaches are discussed. Finally, the review presents strategies focused on targeting non-catalytic domains of PMTs or scaffolding subunits of chromatin complexes. Overall, although targeting PMTs remains a challenge, recent successes in the field are diverse and encouraging.
    MeSH term(s) Animals ; Binding Sites/drug effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Structure ; Protein Methyltransferases/antagonists & inhibitors ; Protein Methyltransferases/metabolism ; Structure-Activity Relationship
    Chemical Substances Enzyme Inhibitors ; Protein Methyltransferases (EC 2.1.1.-)
    Language English
    Publishing date 2016-09-22
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2451-9456
    ISSN (online) 2451-9456
    DOI 10.1016/j.chembiol.2016.07.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Structural Chemistry of Human RNA Methyltransferases.

    Schapira, Matthieu

    ACS chemical biology

    2016  Volume 11, Issue 3, Page(s) 575–582

    Abstract: RNA methyltransferases (RNMTs) play important roles in RNA stability, splicing, and epigenetic mechanisms. They constitute a promising target class that is underexplored by the medicinal chemistry community. Information of relevance to drug design can be ...

    Abstract RNA methyltransferases (RNMTs) play important roles in RNA stability, splicing, and epigenetic mechanisms. They constitute a promising target class that is underexplored by the medicinal chemistry community. Information of relevance to drug design can be extracted from the rich structural coverage of human RNMTs. In this work, the structural chemistry of this protein family is analyzed in depth. Unlike most methyltransferases, RNMTs generally feature a substrate-binding site that is largely open on the cofactor-binding pocket, favoring the design of bisubstrate inhibitors. Substrate purine or pyrimidines are often sandwiched between hydrophobic walls that can accommodate planar ring systems. When the substrate base is laying on a shallow surface, a 5' flanking base is sometimes anchored in a druggable cavity. The cofactor-binding site is structurally more diverse than in protein methyltransferases and more druggable in SPOUT than in Rossman-fold enzymes. Finally, conformational plasticity observed both at the substrate and cofactor binding sites may be a challenge for structure-based drug design. The landscape drawn here may inform ongoing efforts toward the discovery of the first human RNMT inhibitors.
    MeSH term(s) Binding Sites ; Epigenesis, Genetic/physiology ; Gene Expression Regulation, Enzymologic/physiology ; Humans ; Protein Conformation ; tRNA Methyltransferases/genetics ; tRNA Methyltransferases/metabolism
    Chemical Substances tRNA Methyltransferases (EC 2.1.1.-)
    Language English
    Publishing date 2016-03-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.5b00781
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  7. Article: ProxyBind: A compendium of binding sites for proximity-induced pharmacology.

    Rovers, Evianne / Liu, Lihua / Schapira, Matthieu

    Computational and structural biotechnology journal

    2022  Volume 20, Page(s) 6163–6171

    Abstract: Proximity-induced pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new ... ...

    Abstract Proximity-induced pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new therapeutic modality is firmly established by proteolysis targeting chimeras (PROTACs) that bring an E3 ubiquitin ligase in proximity to a target protein to induce ubiquitination and subsequent degradation of the target. The concept can be expanded to induce other post-translational modifications via the recruitment of different types of protein-modifying enzymes. To survey the human proteome for opportunities in proximity pharmacology, we systematically mapped non-catalytic drug binding pockets on the structure of protein-modifying enzymes available from the Protein Databank. In addition to binding sites exploited by previously reported ProxPharm compounds, we identified putative ligandable non-catalytic pockets in 236 kinases, 45 phosphatases, 37 deubiquitinases, 14 methyltransferases, 11 acetyltransferases, 13 glycosyltransferases, 4 deacetylases, 7 demethylases and 2 glycosidases, including cavities occupied by chemical matter that may serve as starting points for future ProxPharm compounds. This systematic survey confirms that proximity pharmacology is a versatile modality with largely unexplored and promising potential and reveals novel opportunities to pharmacologically rewire molecular circuitries. All data is available from the ProxyBind database at https://polymorph.sgc.utoronto.ca/proxybind/index.php.
    Language English
    Publishing date 2022-11-08
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2694435-2
    ISSN 2001-0370
    ISSN 2001-0370
    DOI 10.1016/j.csbj.2022.11.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: ChemBioPort: an online portal to navigate the structure, function and chemical inhibition of the human proteome.

    Liu, Lihua / Rovers, Evianne / Schapira, Matthieu

    Database : the journal of biological databases and curation

    2022  Volume 2022

    Abstract: Chemical probes are important tools to investigate the function of proteins, evaluate their potential as therapeutic targets and provide chemical starting points for drug discovery. As a result, a growing federation of scientists aims to generate ... ...

    Abstract Chemical probes are important tools to investigate the function of proteins, evaluate their potential as therapeutic targets and provide chemical starting points for drug discovery. As a result, a growing federation of scientists aims to generate chemical probes for all human druggable proteins. A diverse array of data typically guides target selection and chemical probe discovery: information on protein function can help prioritize targets, domain architecture can provide insight on druggability, structural data enables molecular design and existing chemical ligands can serve as foundation or inspiration for chemical probe development. But these heterogenous data types are dispersed across a variety of public repositories that are difficult to cross-reference by non-experts. We developed ChemBioPort, an online resource that allows users to combine queries related to the ontology, domain architecture or name of human proteins to produce downloadable tables that integrate information on function, disease association, essentiality, tissue enrichment, domain architecture, structure and chemical ligands of proteins. Users can convert these tables into dendrograms reflecting sequence similarity, onto which they can graphically project all data types, linked via a mouse-click to their original repositories or published articles. This interface will support the growing community of chemical biologists, chemists, cell and structural biologists on their perilous journey from genes to medicines. Database URL: https://chembioport.thesgc.org.
    MeSH term(s) Databases, Factual ; Drug Discovery ; Humans ; Internet Use ; Ligands ; Proteome/antagonists & inhibitors ; Proteome/metabolism
    Chemical Substances Ligands ; Proteome
    Language English
    Publishing date 2022-09-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2496706-3
    ISSN 1758-0463 ; 1758-0463
    ISSN (online) 1758-0463
    ISSN 1758-0463
    DOI 10.1093/database/baac088
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: STRUCTURAL BIOLOGY. Chromatin complex, crystal clear.

    Schapira, Matthieu

    Science (New York, N.Y.)

    2015  Volume 350, Issue 6258, Page(s) 278–279

    MeSH term(s) Chaetomium/metabolism ; Fungal Proteins/chemistry ; Gene Silencing ; Histones/metabolism ; Humans ; Polycomb Repressive Complex 2/chemistry
    Chemical Substances Fungal Proteins ; Histones ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
    Language English
    Publishing date 2015-10-16
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aad5203
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    Zs.A 27: Show issues Location:
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    Zs.MG 77: Show issues

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  10. Article ; Online: Open laboratory notebooks: good for science, good for society, good for scientists.

    Schapira, Matthieu / Harding, Rachel J

    F1000Research

    2019  Volume 8, Page(s) 87

    Abstract: The fundamental goal of the growing open science movement is to increase the efficiency of the global scientific community and accelerate progress and discoveries for the common good. Central to this principle is the rapid disclosure of research outputs ... ...

    Abstract The fundamental goal of the growing open science movement is to increase the efficiency of the global scientific community and accelerate progress and discoveries for the common good. Central to this principle is the rapid disclosure of research outputs in open-access peer-reviewed journals and on pre-print servers. The next bold step in this direction is open laboratory notebooks, where research scientists share their research - including detailed protocols, negative and positive results - online and in near-real-time to synergize with their peers. Here, we highlight the benefits of open lab notebooks to science, society and scientists, and discuss the challenges that this nascent movement is facing. We also present the implementation and progress of our own initiative at openlabnotebooks.org, with more than 20 active contributors after one year of operation.
    Language English
    Publishing date 2019-01-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 2699932-8
    ISSN 2046-1402 ; 2046-1402
    ISSN (online) 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.17710.1
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