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Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists
In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry....
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Published in: | Molecular pharmacology 2008-03, Vol.73 (3), p.789-800 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for
human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent
activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5
antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5
homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish
the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic
potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy
that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists
showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is
being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better
resistance profile. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.107.042101 |