title: Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.
abstract: 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.
authors: Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
authors: Rama
authors: R
authors: Kondru
authors: Jun
authors: J
authors: Zhang
authors: Changhua
authors: C
authors: Ji
authors: Tara
authors: T
authors: Mirzadegan
authors: David
authors: D
authors: Rotstein
authors: Surya
authors: S
authors: Sankuratri
authors: Marianna
authors: M
authors: Dioszegi
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000145:classification* / Q000378:metabolism* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D000077592:Maraviroc; D008561:Membrane Fusion / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055672:Static Electricity; D014162:Transfection; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D010880:Piperidines; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D013141:Spiro Compounds; C506969:TAK-220; D014230:Triazoles; C499671:aplaviroc; C119369:TAK 779; D000077592:Maraviroc; C486781:vicriviroc