Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease
Marielena Vogel Saivish,
Gabriela de Lima Menezes,
Vivaldo Gomes da Costa,
Liliane Nebo,
Gislaine Celestino Dutra da Silva,
Carolina Colombelli Pacca,
Rafael Elias Marques,
Maurício Lacerda Nogueira,
Roosevelt Alves Da Silva
Affiliations
Marielena Vogel Saivish
Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto 15090-000, Brazil
Gabriela de Lima Menezes
Núcleo Colaborativo de Biosistemas, Universidade Federal de Jataí, Jataí 75801-615, Brazil
Vivaldo Gomes da Costa
Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista (UNESP), São José do Rio Preto 15054-000, Brazil
Liliane Nebo
Núcleo Colaborativo de Biosistemas, Universidade Federal de Jataí, Jataí 75801-615, Brazil
Gislaine Celestino Dutra da Silva
Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto 15090-000, Brazil
Carolina Colombelli Pacca
Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista (UNESP), São José do Rio Preto 15054-000, Brazil
Rafael Elias Marques
Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas 13083-100, Brazil
Maurício Lacerda Nogueira
Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto 15090-000, Brazil
Roosevelt Alves Da Silva
Núcleo Colaborativo de Biosistemas, Universidade Federal de Jataí, Jataí 75801-615, Brazil
Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases in developing countries but are not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins are encoded in the flavivirus RNA. The N2B–NS3pro protein complex plays a fundamental role in flavivirus replication and is a promising drug target; however, no flavivirus protease inhibitors have progressed to the preclinical stage. This study analyzed the structural models and plasticity of the NS2B–NS3pro protein complex of five medically important non-dengue flaviviruses (West Nile, Rocio, Ilhéus, yellow fever, and Saint Louis encephalitis). The flavonoids amentoflavone, tetrahydrorobustaflavone, and quercetin were selected for their exceptional binding energies as potential inhibitors of the NS2B–NS3pro protein complex. AutoDock Vina results ranged from −7.0 kcal/mol to −11.5 kcal/mol and the compounds preferentially acted non-competitively. Additionally, the first structural model for the NS2B–NS3pro protein complex was proposed for Ilhéus and Rocio viruses. The NS2B–NS3pro protease is an attractive molecular target for drug development. The three identified natural flavonoids showed great inhibitory potential against the viral species. Nevertheless, further in silico and in vitro studies are required to obtain more information regarding NS2B–NS3pro inhibition by these flavonoids and their therapeutic potential.
