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1.
J Am Chem Soc ; 144(7): 2905-2920, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35142215

RESUMO

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.


Assuntos
Antivirais/farmacologia , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , SARS-CoV-2/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antivirais/metabolismo , Antivirais/farmacocinética , Domínio Catalítico , Chlorocebus aethiops , Proteases 3C de Coronavírus/química , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacocinética , Células Vero
2.
Prostaglandins Other Lipid Mediat ; 107: 26-34, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24045148

RESUMO

Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids.


Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Ácidos Isonipecóticos/farmacologia , Animais , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Concentração Inibidora 50 , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Prostaglandina H2/metabolismo , Prostaglandina-E Sintases , Ratos , Tromboxano B2/metabolismo
3.
Assay Drug Dev Technol ; 9(5): 487-95, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21561373

RESUMO

Microsomal prostaglandin E(2) synthase-1 (MPGES1) catalyzes the formation of prostaglandin E(2) from the endoperoxide prostaglandin H(2). MPGES1 expression is induced in inflammatory diseases, and this enzyme is regarded as a potential drug target. To aid in the drug discovery effort, a simple method for determination of inhibition mechanism and potency toward both prostaglandin H(2) and glutathione (GSH) has been developed. Using an assay with thiobarbituric acid-based detection, the inhibitory effects of six MPGES1 inhibitors were evaluated. The IC(50) values obtained at three substrate (S) concentrations ([S]K(M)) were used to estimate inhibition modality and inhibition constant values. This facilitated strategy is a useful and general screening method to evaluate the inhibitory effects of new drug compounds.


Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Inibidores Enzimáticos/metabolismo , Oxirredutases Intramoleculares/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Fluorescência , Glutationa/análise , Humanos , Indóis/análise , Indóis/farmacocinética , Indóis/farmacologia , Concentração Inibidora 50 , Oxirredutases Intramoleculares/análise , Oxirredutases Intramoleculares/fisiologia , Malondialdeído/metabolismo , Modelos Teóricos , Terapia de Alvo Molecular , Farmacocinética , Prostaglandina H2/antagonistas & inibidores , Prostaglandina H2/metabolismo , Prostaglandina-E Sintases , Tiobarbitúricos/metabolismo
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