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
| Autor: | M. Maccoss, Paul E. Finke, Bruce L. Daugherty, Youmin Weng, Di Salvo J, Julie A. DeMartino, Christopher L. Lynch, Laurie A. Castonguay, Marty S. Springer, J. J. Hale, Sander G. Mills, Adolfsen W, Charles G. Caldwell, Ruth Kilburn |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Rhodopsin Pyrrolidines Receptors CCR5 Molecular model Stereochemistry Chemokine receptor CCR5 Molecular Sequence Data CHO Cells Binding Competitive Biochemistry Protein Structure Secondary Structure-Activity Relationship chemistry.chemical_compound Piperidines Cricetinae Animals Humans Amino Acid Sequence Binding site Alanine Binding Sites Sequence Homology Amino Acid biology Aryl Amides Quaternary Ammonium Compounds Transmembrane domain Amino Acid Substitution chemistry Docking (molecular) CCR5 Receptor Antagonists Butanes Mutagenesis Site-Directed biology.protein Cattle Pharmacophore |
| Zdroj: | Biochemistry. 42:1544-1550 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi026639s |
| Popis: | 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]. |
| Databáze: | OpenAIRE |
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