Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2.

Autor: Purificação AD; Protein Crystallography Laboratory, Department of Biomolecular Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil., Silva-Mendonça S; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Cruz LV; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Sacramento CQ; Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil., Temerozo JR; Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil., Fintelman-Rodrigues N; Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil., de Freitas CS; Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil., Godoi BF; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirao Preto 05508-060, SP, Brazil., Vaidergorn MM; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirao Preto 05508-060, SP, Brazil., Leite JA; Laboratory of Tropical Diseases, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, Unicamp, Campinas 13.083-857, SP, Brazil., Salazar Alvarez LC; Laboratory of Tropical Diseases, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, Unicamp, Campinas 13.083-857, SP, Brazil., Freitas MV; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Silvac MFB; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil.; Laboratory of Cheminformatics, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Martin BA; Innovation Center in Nanostructured Systems and Topical Administration (NanoTop), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil., Lopez RFV; Innovation Center in Nanostructured Systems and Topical Administration (NanoTop), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil., Neves BJ; Laboratory of Cheminformatics, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Costa FTM; Laboratory of Tropical Diseases, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, Unicamp, Campinas 13.083-857, SP, Brazil., Souza TML; Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil., da Silva Emery F; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirao Preto 05508-060, SP, Brazil., Andrade CH; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil.; Center for Excellence in Artificial Intelligence (CEIA), Institute of Informatics, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil., Nonato MC; Protein Crystallography Laboratory, Department of Biomolecular Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto 05508-060, SP, Brazil.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2024 Feb 28; Vol. 9 (10), pp. 11418-11430. Date of Electronic Publication: 2024 Feb 28 (Print Publication: 2024).
DOI: 10.1021/acsomega.3c07845
Abstrakt: The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase ( Hs DHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent Hs DHODH inhibition with IC 50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC 50 ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent Hs DHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.
Competing Interests: The authors declare no competing financial interest.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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