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Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Chem. Inf. Model. 2024, 64, 2, 393-411
    Computational Chemistry

    Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach
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    • Mateus Sá Magalhães Serafim
      Mateus Sá Magalhães Serafim
      Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Mateus Sá Magalhães Serafim
    • Thales Kronenberger
      Thales Kronenberger
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany
      Excellence Cluster “Controlling Microbes to Fight Infections” (CMFI), Tübingen 72076, Germany
      School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland
      More by Thales Kronenberger
      Orcidhttps://orcid.org/0000-0001-6933-7590
    • Rafael Eduardo Oliveira Rocha
      Rafael Eduardo Oliveira Rocha
      Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Rafael Eduardo Oliveira Rocha
    • Amanda Del Rio Abreu Rosa
      Amanda Del Rio Abreu Rosa
      Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Amanda Del Rio Abreu Rosa
    • Thaysa Lara Gonçalves Mello
      Thaysa Lara Gonçalves Mello
      Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Thaysa Lara Gonçalves Mello
    • Antti Poso
      Antti Poso
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany
      School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland
      Department of Medical Oncology and Pneumology, University Hospital of Tübingen, Tübingen 70211, Germany
      More by Antti Poso
      Orcidhttps://orcid.org/0000-0003-4196-4204
    • Rafaela Salgado Ferreira
      Rafaela Salgado Ferreira
      Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Rafaela Salgado Ferreira
      Orcidhttps://orcid.org/0000-0003-3324-0601
    • Jonatas Santos Abrahão
      Jonatas Santos Abrahão
      Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Jonatas Santos Abrahão
    • Erna Geessien Kroon
      Erna Geessien Kroon
      Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      More by Erna Geessien Kroon
    • Bruno Eduardo Fernandes Mota*
      Bruno Eduardo Fernandes Mota
      Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      *Email: [email protected]
      More by Bruno Eduardo Fernandes Mota
    • Vinícius Gonçalves Maltarollo*
      Vinícius Gonçalves Maltarollo
      Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG 31270-901, Brazil
      *Email: [email protected]
      More by Vinícius Gonçalves Maltarollo
      Orcidhttps://orcid.org/0000-0001-9675-5907
    Other Access OptionsSupporting Information (1)

    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2024, 64, 2, 393–411
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jcim.3c01505
    Published January 9, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks of DENV, Zika virus (ZIKV), and yellow fever virus (YFV), the lack of antiviral drugs, and limitations on vaccine usage emphasize the need for novel antiviral research. Here, we propose a consensus virtual screening approach to discover potential protease inhibitors (NS3pro) against different flavivirus. We employed an in silico combination of a hologram quantitative structure–activity relationship (HQSAR) model and molecular docking on characterized binding sites followed by molecular dynamics (MD) simulations, which filtered a data set of 7.6 million compounds to 2,775 hits. Lastly, docking and MD simulations selected six final potential NS3pro inhibitors with stable interactions along the simulations. Five compounds had their antiviral activity confirmed against ZIKV, YFV, DENV-2, and DENV-3 (ranging from 4.21 ± 0.14 to 37.51 ± 0.8 μM), displaying aggregator characteristics for enzymatic inhibition against ZIKV NS3pro (ranging from 28 ± 7 to 70 ± 7 μM). Taken together, the compounds identified in this approach may contribute to the design of promising candidates to treat different flavivirus infections.

    Copyright © 2024 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.3c01505.

    • HQSAR data (Figure S1 and Tables S1–S3), pharmacophore’s docking and MD simulations (Figure S2), VS’ selected compounds (Figure S3), pretreatment assays (Figure S4), virucidal activity (Figure S5), concentration–response curves (Figure S6), and NS3pro cleavage site (Figure S7). Lastly, the predicted residues with FTMap (Table S4), bonds with the pharmacophore (Table S5), and pharmacokinetics and toxicity parameters (Table S6) (PDF)

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    Cited By

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    This article is cited by 1 publications.

    1. Kun Li, You Lv, Rongzhang Wu, Zhenwu Yu, Yulin Liang, Zecong Yu, Ruobing Liang, Liangfu Tang, Hongyu Chen, Zhijin Fan. Fungicidal Activity of Novel 6-Isothiazol-5-ylpyrimidin-4-amine-Containing Compounds Targeting Complex I Reduced Nicotinamide Adenine Dinucleotide Oxidoreductase. Journal of Agricultural and Food Chemistry 2024, 72 (40) , 22082-22091. https://doi.org/10.1021/acs.jafc.4c07259
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2024, 64, 2, 393–411
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jcim.3c01505
    Published January 9, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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