RT Journal Article
SR Electronic
T1 Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 789
OP 800
DO 10.1124/mol.107.042101
VO 73
IS 3
A1 Rama Kondru
A1 Jun Zhang
A1 Changhua Ji
A1 Tara Mirzadegan
A1 David Rotstein
A1 Surya Sankuratri
A1 Marianna Dioszegi
YR 2008
UL http://molpharm.aspetjournals.org/content/73/3/789.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics