Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase.
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.
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute,  National Institutes of Health , 37 Convent Drive, Bethesda, Maryland 20892, United States.
Mathieu
M
Métifiot
Kasthuraiah
K
Maddali
Barry C
BC
Johnson
Stephen
S
Hare
Steven J
SJ
Smith
Xue Zhi
XZ
Zhao
Christophe
C
Marchand
Terrence R
TR
Burke
Stephen H
SH
Hughes
Peter
P
Cherepanov
Yves
Y
Pommier
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D054833:Isoindoles / Q000737:chemistry* / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D000998:Antiviral Agents; D019428:HIV Integrase Inhibitors; D054833:Isoindoles; D013449:Sulfonamides; C581985:XZ-259