Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 11, Pages 3275-3279Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.04.048
Keywords
HIV; Integrase; Inhibitor design; Docking model; Binding mechanism
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Funding
- Center for Drug Design at the University of Minnesota
- Center for Cancer Research, National Cancer Institute, NIH
- NATIONAL CANCER INSTITUTE [ZIABC007333] Funding Source: NIH RePORTER
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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.
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