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  1. Article ; Online: Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2: Virtual screening and structure based drug design.

    Meyer-Almes, Franz-Josef

    Computational biology and chemistry

    2020  Volume 88, Page(s) 107351

    Abstract: 3CL proteases ( ... ...

    Abstract 3CL proteases (3CL
    MeSH term(s) Betacoronavirus/drug effects ; Betacoronavirus/enzymology ; COVID-19 ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Cysteine Endopeptidases ; Databases, Factual ; Drug Design ; Drug Repositioning ; Humans ; Models, Molecular ; Molecular Docking Simulation ; Pandemics ; Pneumonia, Viral/drug therapy ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protein Conformation ; SARS-CoV-2 ; Viral Nonstructural Proteins/antagonists & inhibitors
    Chemical Substances Protease Inhibitors ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Keywords covid19
    Language English
    Publishing date 2020-07-31
    Publishing country England
    Document type Journal Article
    ISSN 1476-928X
    ISSN (online) 1476-928X
    DOI 10.1016/j.compbiolchem.2020.107351
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Continuous enzyme activity assay for high-throughput classification of histone deacetylase 8 inhibitors.

    Schweipert, Markus / Amurthavasan, Anuja / Meyer-Almes, Franz-Josef

    Exploration of targeted anti-tumor therapy

    2023  Volume 4, Issue 3, Page(s) 447–459

    Abstract: Aim: Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere ... ...

    Abstract Aim: Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere with the enzyme activity of KDAC8. These compounds have been identified under equilibrium or near equilibrium conditions for inhibitor binding to the target enzyme. This study aims for the classification of KDAC8 inhibitors according to the mode of action and identification of most promising lead compounds for drug development.
    Methods: A continuous enzyme activity assay is used to monitor inhibition kinetics.
    Results: A high-throughput continuous KDAC8 activity assay is developed that provides additional mechanistic information about enzyme inhibition enabling the classification of KDAC8 inhibitors according to their mode of action. Fast reversible inhibitors act as a molecular chaperone and are capable to rescue the enzyme activity of misfolded KDAC8, while covalent inactivators and slow dissociating inhibitors do not preserve KDAC8 activity.
    Conclusions: The application of continuous KDAC8 activity assay reveals additional information about the mode of interaction with inhibitors, which can be used to classify KDAC8 inhibitors according to their mode of action. The approach is compatible with the high-throughput screening of compound libraries. Fast reversible inhibitors of KDAC8 act as molecular chaperones and recover enzyme activity from misfolded protein conformations. In contrast, slow-binding inhibitors and covalent inactivators of KDAC8 are not capable to recover enzyme activity.
    Language English
    Publishing date 2023-06-30
    Publishing country United States
    Document type Journal Article
    ISSN 2692-3114
    ISSN (online) 2692-3114
    DOI 10.37349/etat.2023.00144
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  3. Article ; Online: Significance of Five-Membered Heterocycles in Human Histone Deacetylase Inhibitors.

    Frühauf, Anton / Behringer, Martin / Meyer-Almes, Franz-Josef

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 15

    Abstract: Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical ... ...

    Abstract Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical properties and biological effects of five-membered heterocycles have positioned them as key structural motifs in numerous clinically effective drugs. Hence, the exploration of five-ring heterocycles remains an important research area in medicinal chemistry, with the aim of discovering new therapeutic agents for various diseases. This review addresses the incorporation of heteroatoms such as nitrogen, oxygen and sulfur into the aromatic ring of these heterocyclic compounds, enhancing their polarity and facilitating both aromatic stacking interactions and the formation of hydrogen bonds. Histone deacetylases are present in numerous multiprotein complexes within the epigenetic machinery and play a central role in various cellular processes. They have emerged as important targets for cancer, neurodegenerative diseases and other therapeutic indications. In histone deacetylase inhibitors (HDACi's), five-ring heterocycles perform various functions as a zinc-binding group, a linker or head group, contributing to binding activity and selective recognition. This review focuses on providing an up-to-date overview of the different five-membered heterocycles utilized in HDACi motifs, highlighting their biological properties. It summarizes relevant publications from the past decade, offering insights into the recent advancements in this field of research.
    MeSH term(s) Humans ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry ; Neoplasms ; Heterocyclic Compounds/pharmacology ; Heterocyclic Compounds/chemistry ; Histone Deacetylases
    Chemical Substances Histone Deacetylase Inhibitors ; Heterocyclic Compounds ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2023-07-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28155686
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  4. Article ; Online: Continuous enzyme activity assay for high-throughput classification of histone deacetylase 8 inhibitors

    Markus Schweipert / Anuja Amurthavasan / Franz-Josef Meyer-Almes

    Exploration of Targeted Anti-tumor Therapy, Vol 4, Iss 3, Pp 447-

    2023  Volume 459

    Abstract: Aim: Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere ... ...

    Abstract Aim: Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere with the enzyme activity of KDAC8. These compounds have been identified under equilibrium or near equilibrium conditions for inhibitor binding to the target enzyme. This study aims for the classification of KDAC8 inhibitors according to the mode of action and identification of most promising lead compounds for drug development. Methods: A continuous enzyme activity assay is used to monitor inhibition kinetics. Results: A high-throughput continuous KDAC8 activity assay is developed that provides additional mechanistic information about enzyme inhibition enabling the classification of KDAC8 inhibitors according to their mode of action. Fast reversible inhibitors act as a molecular chaperone and are capable to rescue the enzyme activity of misfolded KDAC8, while covalent inactivators and slow dissociating inhibitors do not preserve KDAC8 activity. Conclusions: The application of continuous KDAC8 activity assay reveals additional information about the mode of interaction with inhibitors, which can be used to classify KDAC8 inhibitors according to their mode of action. The approach is compatible with the high-throughput screening of compound libraries. Fast reversible inhibitors of KDAC8 act as molecular chaperones and recover enzyme activity from misfolded protein conformations. In contrast, slow-binding inhibitors and covalent inactivators of KDAC8 are not capable to recover enzyme activity.
    Keywords continuous enzyme activity assay ; histone deacetylases ; binding mode ; binding mechanism ; adverse effects ; high-throughput screening ; Internal medicine ; RC31-1245
    Subject code 500 ; 540
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Open Exploration Publishing Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors.

    Jänsch, Niklas / Lang, Kim Leoni / Meyer-Almes, Franz-Josef

    International journal of molecular sciences

    2022  Volume 23, Issue 19

    Abstract: HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act ...

    Abstract HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a "switch" that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors.
    MeSH term(s) Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylases/metabolism ; Humans ; Isoenzymes ; Methionine ; Neuroblastoma ; Repressor Proteins
    Chemical Substances Histone Deacetylase Inhibitors ; Isoenzymes ; Repressor Proteins ; Methionine (AE28F7PNPL) ; HDAC8 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2022-10-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms231911775
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  6. Article ; Online: Determination of the binding mechanism of histone deacetylase inhibitors.

    Meyer-Almes, Franz-Josef

    Chemical biology & drug design

    2018  Volume 93, Issue 6, Page(s) 1214–1250

    Abstract: This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small-molecule inhibitors, or substrates interact with zinc-containing bacterial or human members of the histone deacetylase family (HDACs). ... ...

    Abstract This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small-molecule inhibitors, or substrates interact with zinc-containing bacterial or human members of the histone deacetylase family (HDACs). These methods include biochemical and biophysical approaches and can be subdivided into equilibrium and kinetic methods. More information about the exact mode of action can be obtained by combining these methods with specific mutant variants of the enzymes and/or series of structural similar ligands. All available equilibrium and kinetic data including additional information from 3D structures of HDAC-ligand complexes can be beneficially combined in a data analysis procedure called Integrated Global-Fit analysis eventually providing the most likely binding mechanism.
    MeSH term(s) Histone Deacetylase Inhibitors/metabolism ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Kinetics ; Ligands ; Mutation ; Protein Binding ; Zinc/metabolism
    Chemical Substances Histone Deacetylase Inhibitors ; Ligands ; Histone Deacetylases (EC 3.5.1.98) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2018-12-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 2216600-2
    ISSN 1747-0285 ; 1747-0277
    ISSN (online) 1747-0285
    ISSN 1747-0277
    DOI 10.1111/cbdd.13449
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  7. Article ; Online: Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2

    Meyer-Almes, Franz-Josef

    Computational Biology and Chemistry

    Virtual screening and structure based drug design

    2020  Volume 88, Page(s) 107351

    Keywords Organic Chemistry ; Biochemistry ; Structural Biology ; Computational Mathematics ; covid19
    Language English
    Publisher Elsevier BV
    Publishing country us
    Document type Article ; Online
    ZDB-ID 2110171-1
    ISSN 1476-9271
    ISSN 1476-9271
    DOI 10.1016/j.compbiolchem.2020.107351
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Design and synthesis of peptides as stabilizers of histone deacetylase 4.

    Lill, Annika / Schweipert, Markus / Nehls, Thomas / Wurster, Eva / Lermyte, Frederik / Meyer-Almes, Franz-Josef / Schmitz, Katja

    Journal of peptide science : an official publication of the European Peptide Society

    2024  , Page(s) e3603

    Abstract: Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific ... ...

    Abstract Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT-motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit K
    Language English
    Publishing date 2024-04-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 1234416-3
    ISSN 1099-1387 ; 1075-2617
    ISSN (online) 1099-1387
    ISSN 1075-2617
    DOI 10.1002/psc.3603
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6200: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  9. Article: Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2: Virtual screening and structure based drug design

    Meyer-Almes, Franz-Josef

    Comput Biol Chem

    Abstract: 3CL proteases (3CLpro) are only found in RNA viruses and have a central role in polyprotein processing during replication. Therefore, 3CLpro has emerged as promising drug target for therapeutic treatment of infections caused by Coronaviruses. In the ... ...

    Abstract 3CL proteases (3CLpro) are only found in RNA viruses and have a central role in polyprotein processing during replication. Therefore, 3CLpro has emerged as promising drug target for therapeutic treatment of infections caused by Coronaviruses. In the light of the recent major outbreak of the SARS-CoV-2 virus and the continuously rising numbers of infections and casualties, there is an urgent need for quickly available drugs or vaccines to stop the current COVID-19 pandemic. Repurposing of approved drugs as 3CLpro inhibitors could dramatically shorten the period up to approval as therapeutic against SARS-CoV-2, since pharmacokinetics and toxicity is already known. Several known drugs, e.g. oxytetracycline, doxorubicin, kanamycin, cefpiramide, teniposide, proanthocyanidin and salvianolic acid B, but also not-approved active compounds from the ZINC15 library were identified as new potential inhibitors of 3CLpro by using different complementary virtual screening and docking approaches. These compounds have the potential to be further optimized using structure based drug design as demonstrated for oxytetracycline.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #715245
    Database COVID19

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  10. Article ; Online: Synthesis and Characterization of Reversible Covalent HDAC4 Inhibitors.

    Frühauf, Anton / Wolff, Benjamin / Schweipert, Markus / Meyer-Almes, Franz-Josef

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2589, Page(s) 207–221

    Abstract: Cyanoacrylates define a class of inhibitors which are capable to form a transient covalent bond with a cysteine flanking the binding site, thereby increasing the residence time and prolonging the inhibitory effect on the target protein under ... ...

    Abstract Cyanoacrylates define a class of inhibitors which are capable to form a transient covalent bond with a cysteine flanking the binding site, thereby increasing the residence time and prolonging the inhibitory effect on the target protein under nonequilibrium conditions. Herein, we describe the synthetic access to cyanoacrylate-based HDAC4 inhibitors and the procedures for the characterization of the transient nature of the covalent bond between cyanoacrylates and thiols or cysteines in HDAC4.
    MeSH term(s) Cysteine/metabolism ; Binding Sites ; Cyanoacrylates ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry
    Chemical Substances Cysteine (K848JZ4886) ; Cyanoacrylates ; Histone Deacetylase Inhibitors
    Language English
    Publishing date 2022-10-18
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2788-4_14
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