Desenho racional de inibidores da protease principal do SARS-CoV-2
Data
2023-12-12
Autores
Montilla, Rafael Augusto Girao 
Orientadores
Wurtele, Martin Alejandro
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Este estudo utiliza o software Gnina para realizar o docking molecular para investigar
as interações moleculares de novos compostos sintetizados através da reação de Ugi. O foco
está no desenvolvimento de inibidores não covalentes direcionados à Protease Principal
(Mpro) do SARS-CoV-2. Os resultados de docking são empregados para calcular energias
livres de ligação, e esses valores são correlacionados com a concentração inibitória (IC50).
Para estabelecer esta correlação, simulações de dockings virtual são conduzidas para
compostos conhecidos da literatura com valores medidos de IC50 contra SARS-CoV-2 Mpro.
Todos os compostos avaliados, pertencentes à mesma classe de inibidores, são caracterizados
como pseudopeptídeos não covalentes. A análise dos dockins revela insights sobre os
aspectos estruturais da inibição do Mpro, enfatizando os bolsões S1, S2, S3 e S4 no sítio
ativo. O estudo identifica dois leads potenciais; ambos os compostos exibem um modo de
ligação invertido em comparação com os peptídeos clivados por Mpro. A abordagem de
bioinformática estrutural aqui empregada fornece informações valiosas para o projeto de
novos inibidores não covalentes contra SARS-CoV-2 Mpro. É necessária validação adicional
através de testes in vitro para confirmar o potencial inibitório dos compostos concebidos. Este
estudo contribui para a nossa compreensão das interações moleculares envolvidas na inibição
do SARS-CoV-2 Mpro e estabelece as bases para o desenvolvimento de terapêutica antiviral
eficaz.
This study utilizes the Gnina software for molecular docking to investigate the molecular interactions of novel compounds synthesized through the Ugi reaction. The focus is on designing non-covalent inhibitors targeting the Main Protease (Mpro) of SARS-CoV-2. Docking results are employed to calculate binding free energies, and these values are correlated with inhibitory concentration (IC50). To establish this correlation, virtual docking simulations are conducted for known literature compounds with measured IC50 values against SARS-CoV-2 Mpro. All evaluated compounds, belonging to the same class of inhibitors, are characterized as non-covalent pseudo-peptides. The docking analysis reveals insights into the structural aspects of Mpro inhibition, emphasizing the pockets S1, S2, S3, and S4 in the active site. The study identifies two potential leads; both compounds exhibit an inverted binding mode compared to the peptides cleaved by Mpro. The structural bioinformatics approach employed here provides valuable information for the design of novels non-covalent inhibitors against SARS-CoV-2 Mpro. Further validation through in vitro testing is required to confirm the inhibitory potential of the designed compounds. This study contributes to our understanding of the molecular interactions involved in SARS-CoV-2 Mpro inhibition and lays the foundation for the development of effective antiviral therapeutics.
This study utilizes the Gnina software for molecular docking to investigate the molecular interactions of novel compounds synthesized through the Ugi reaction. The focus is on designing non-covalent inhibitors targeting the Main Protease (Mpro) of SARS-CoV-2. Docking results are employed to calculate binding free energies, and these values are correlated with inhibitory concentration (IC50). To establish this correlation, virtual docking simulations are conducted for known literature compounds with measured IC50 values against SARS-CoV-2 Mpro. All evaluated compounds, belonging to the same class of inhibitors, are characterized as non-covalent pseudo-peptides. The docking analysis reveals insights into the structural aspects of Mpro inhibition, emphasizing the pockets S1, S2, S3, and S4 in the active site. The study identifies two potential leads; both compounds exhibit an inverted binding mode compared to the peptides cleaved by Mpro. The structural bioinformatics approach employed here provides valuable information for the design of novels non-covalent inhibitors against SARS-CoV-2 Mpro. Further validation through in vitro testing is required to confirm the inhibitory potential of the designed compounds. This study contributes to our understanding of the molecular interactions involved in SARS-CoV-2 Mpro inhibition and lays the foundation for the development of effective antiviral therapeutics.
Descrição
Citação
Desenho Racional de Inibidores Antivirais, Rafael Montilla, Martin Wurtele, UNIFESP, 2023.