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

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• 作者：Mathieu M茅tifiot ; Kasthuraiah Maddali ; Barry C. Johnson ; Stephen Hare ; Steven J. Smith ; Xue Zhi Zhao ; Christophe Marchand ; Terrence R. Burke ; Jr. ; Stephen H. Hughes ; Peter Cherepanov ; Yves Pommier
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：January 18, 2013
• 年：2013
• 卷：8
• 期：1
• 页码：209-217
• 全文大小：703K
• 年卷期：v.8,no.1(January 18, 2013)
• ISSN：1554-8937

文摘

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-Mg²⁺-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.