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

Jing Tang; Kasthuraiah Maddali; Yves Pommier; Yuk Y. Sham; Zhengqiang Wang

doi:10.1016/j.bmcl.2010.04.048

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

Jing Tang
, Kasthuraiah Maddali
, Yves Pommier
, Yuk Y. Sham
, Zhengqiang Wang

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	3275-3279
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2010.04.048
State	Published - Jun 1 2010

Bibliographical note

Funding 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Binding mechanism
Docking model
HIV
Inhibitor design
Integrase

Publisher link

10.1016/j.bmcl.2010.04.048

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abstract = "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.",

keywords = "Binding mechanism, Docking model, HIV, Inhibitor design, Integrase",

author = "Jing Tang and Kasthuraiah Maddali and Yves Pommier and Sham, \{Yuk Y.\} and Zhengqiang Wang",

note = "Funding 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. ",

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T2 - Docking model revisited

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AU - Maddali, Kasthuraiah

AU - Pommier, Yves

AU - Sham, Yuk Y.

AU - Wang, Zhengqiang

N1 - Funding 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.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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.

AB - 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.

KW - Binding mechanism

KW - Docking model

KW - HIV

KW - Inhibitor design

KW - Integrase

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

Abstract

Bibliographical note

UN SDGs

Keywords

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