Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Tang, Jing¹  Maddali, Kasthuraiah²  Pommier, Yves²  Sham, Yuk Y.¹  Wang, Zhengqiang¹ 

[1] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA

[2] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA

关键词: HIV;    Integrase;    Inhibitor design;    Docking model;    Binding mechanism;   

DOI  :  10.1016/j.bmcl.2010.04.048

来源: Elsevier

【 摘 要 】

A series of dihydroxypyrimidine (DHP) derivatives were designed as inhibitors of HIV integrase (IN) based on known homology models. Through chemical synthesis and biochemical assays it was found that the activity profile of these compounds largely deviates from predictions with existing models. With the recently disclosed IN crystal structure of prototype foamy virus (PFV), a new HIV IN homology model was constructed featuring a critical IN/DNA interface previously lacking. With this new model, docking results completely corroborated observed biological activities. This new model should provide a more accurate and improved platform for the design of new inhibitors of HIV IN. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free