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.
Bibliographical noteFunding Information:
This research was supported by the Center for Drug Design at the University of Minnesota and by the Center for Cancer Research, National Cancer Institute, NIH. We thank Professor Robert Vince for discussion and the University of Minnesota Supercomputing Institute for providing computational resources.
- Binding mechanism
- Docking model
- Inhibitor design