Activities, Crystal Structures, and Molecular Dynamics of Dihydro-1H-isoindole Derivatives, Inhibitors of HIV-1 lntegrase

作者：Metifiot Mathieu; Maddali Kasthuraiah; Johnson Barry C; Hare Stephen; Smith Steven J; Zhao Xue Zhi; Marchand Christophe; Burke Terrence R Jr; Hughes Stephen H; Cherepanov Peter; Pommier Yves^*

来源：ACS Chemical Biology, 2013, 8(1): 209-217.

DOI：10.1021/cb300471n

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-Me2+-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.

• 出版日期2013-1