Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors-Reference-Cited by-同舟云学术

Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors

Published:2023-06 Issue:11 Volume:15 Page:959-985
ISSN:1756-8919
Container-title:Future Medicinal Chemistry
language:en
Short-container-title:Future Medicinal Chemistry

Author:

Maltarollo Vinícius Gonçalves¹^ORCID,da Silva Elany Barbosa²^ORCID,Kronenberger Thales³⁴⁵⁶^ORCID,Sena Andrade Marina Mol¹,de Lima Marques Gabriel V¹^ORCID,Cândido Oliveira Nereu J¹,Santos Lucianna H⁷,Oliveira Rezende Júnior Celso de⁸⁹,Cassiano Martinho Ana C⁸,Skinner Danielle²,Fajtová Pavla²¹⁰,M Fernandes Thaís H²¹¹¹²,Silveira dos Santos Eduardo da¹¹¹²,Rodrigues Gazolla Poliana A¹³,Martins de Souza Ana P¹³,da Silva Milene Lopes¹³,dos Santos Fabíola S¹³,Lavorato Stefânia N¹¹⁴,Oliveira Bretas Ana C¹,Carvalho Diogo Teixeira¹,Franco Lucas Lopardi¹,Luedtke Stephanie²,Giardini Miriam A²^ORCID,Poso Antti³⁴⁵⁶^ORCID,Dias Luiz C⁹,Podust Larissa M²,Alves Ricardo J¹,McKerrow James²,Andrade Saulo F¹¹¹²,Teixeira Róbson R¹³,Siqueira-Neto Jair L²,O’Donoghue Anthony²,de Oliveira Renata B¹^ORCID,Ferreira Rafaela S⁷^ORCID

Affiliation:

1. Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, 31270-901, Brazil

2. Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0657, USA

3. Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen 72076, Germany

4. Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided & Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, 72076, Germany

5. Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, Tübingen, 72076, Germany

6. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland

7. Department of Biochemistry & Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

8. Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, 38400-902, Brazil

9. Instituto de Química, Universidade Estadual de Campinas, Campinas, São Paulo, 13083-970, Brazil

10. Institute of Organic Chemistry & Biochemistry, Academy of Sciences of the Czech Republic, Prague, 16610, Czech Republic

11. Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, 90160-093, Brazil

12. Pharmaceutical Synthesis Group (PHARSG), Departamento de Produção de Matéria-Prima, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, 90160-093, Brazil

13. Grupo de Síntese e Pesquisa de Compostos Bioativos (GSPCB), Departamento de Química, Universidade Federal de Viçosa, Viçosa, Minas Gerais, 36570-900, Brazil

14. Centro das Ciências Biológicas e da Saúde, Universidade Federal do Oeste da Bahia, Barreiras, Bahia, 47810-047, Brazil

Abstract

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4–3 μM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Bundesministerium für Bildung und Forschung

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Fundação de Amparo à Pesquisa do Estado de Minas Gerais

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

Link

https://www.future-science.com/doi/pdf/10.4155/fmc-2023-0034

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