Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase.
ACS Chem Biol
; 8(1): 209-17, 2013 Jan 18.
Article
em En
| MEDLINE
| ID: mdl-23075516
ABSTRACT
On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Inibidores de Integrase de HIV
/
Isoindóis
/
Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos