. 2023 Jun;15(11):959-985.

doi: 10.4155/fmc-2023-0034. Epub 2023 Jul 12.

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

Vinícius Gonçalves Maltarollo¹, Elany Barbosa da Silva², Thales Kronenberger^{3

4

5

6}, Marina Mol Sena Andrade¹, Gabriel V de Lima Marques¹, Nereu J Cândido Oliveira¹, Lucianna H Santos⁷, Celso de Oliveira Rezende Júnior^{8

9}, Ana C Cassiano Martinho⁸, Danielle Skinner², Pavla Fajtová^{2

10}, Thaís H M Fernandes^{2

11

12}, Eduardo da Silveira Dos Santos^{11

12}, Poliana A Rodrigues Gazolla¹³, Ana P Martins de Souza¹³, Milene Lopes da Silva¹³, Fabíola S Dos Santos¹³, Stefânia N Lavorato^{1

14}, Ana C Oliveira Bretas¹, Diogo Teixeira Carvalho¹, Lucas Lopardi Franco¹, Stephanie Luedtke², Miriam A Giardini², Antti Poso^{3

4

5

6}, Luiz C Dias⁹, Larissa M Podust², Ricardo J Alves¹, James McKerrow², Saulo F Andrade^{11

12}, Róbson R Teixeira¹³, Jair L Siqueira-Neto², Anthony O'Donoghue², Renata B de Oliveira¹, Rafaela S Ferreira⁷

Affiliations

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.

PMID: 37435731
DOI: 10.4155/fmc-2023-0034

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

Vinícius Gonçalves Maltarollo et al. Future Med Chem. 2023 Jun.

. 2023 Jun;15(11):959-985.

doi: 10.4155/fmc-2023-0034. Epub 2023 Jul 12.

Authors

Affiliations

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.

PMID: 37435731
DOI: 10.4155/fmc-2023-0034

Abstract

Aim: Discovery of novel SARS-CoV-2 main protease (M^pro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover M^pro 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 M^pro with IC₅₀ values of 0.4-3 μM. They were also shown to inhibit SARS-CoV-1 M^pro and human cathepsin L. Molecular dynamics simulations indicated the stability of the M^pro 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 M^pro inhibitors.

Keywords: Mpro; SARS-CoV-2; computer-aided drug design; coronavirus; molecular docking; molecular dynamics simulations; protease inhibitors; virtual screening.

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

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

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