Cyclic amide bioisosterism: strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.
Bioorg Med Chem Lett
; 20(15): 4614-9, 2010 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-20584604
ABSTRACT
Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Tiofenos
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Proteínas não Estruturais Virais
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Hepacivirus
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Inibidores Enzimáticos
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Amidas
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article