Binding of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket.
The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template [Palczewski, K., et al. (2000) Science 289, 739-745]. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 [Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644].
Castonguay
Laurie A
LA
Department of Molecular SystemsMerck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. laurie_castonguay@merck.com
Weng
Youmin
Y
Adolfsen
William
W
Di Salvo
Jerry
J
Kilburn
Ruth
R
Caldwell
Charles G
CG
Daugherty
Bruce L
BL
Finke
Paul E
PE
Hale
Jeffrey J
JJ
Lynch
Christopher L
CL
Mills
Sander G
SG
MacCoss
Malcolm
M
Springer
Martin S
MS
DeMartino
Julie A
JA
D000409:Alanine / Q000235:genetics; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics; D002073:Butanes / Q000737:chemistry*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010880:Piperidines / Q000737:chemistry*; D017433:Protein Structure, Secondary / Q000235:genetics; D011759:Pyrrolidines / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000577:Amides; D002073:Butanes; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D012243:Rhodopsin; C119369:TAK 779; D000409:Alanine