CCR2: Characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach

Journal of Medicinal Chemistry

Volumn 46, Issue 19, 2003, Pages 4070-4086

  Berkhout, Theo A ^a   Blaney, Frank E ^a   Bridges, Angela M ^a   Cooper, David G ^a   Forbes, Ian T ^a   Gribble, Andrew D ^a   Groot, Pieter H E ^a   Hardy, Adam ^a   Ife, Robert J ^a   Kaur, Rejbinder ^a   Moores, Kitty E ^a   Shillito, Helen ^a   Willetts, Jennifer ^a   Witherington, Jason ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; IMMUNOMODULATING AGENT; MONOCYTE CHEMOTACTIC PROTEIN 1; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; RHODOPSIN; RS 504393; SB 282241; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CHEMOTAXIS; CHO CELL; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG SCREENING; HUMAN; HUMAN CELL; IMMUNOMODULATION; LIGAND BINDING; MONOCYTE; NONHUMAN; NUCLEOTIDE SEQUENCE; SITE DIRECTED MUTAGENESIS; STRUCTURE ACTIVITY RELATION; THEORETICAL MODEL;

AMINO ACID SUBSTITUTION; ANIMALS; BINDING SITES; BINDING, COMPETITIVE; CATTLE; CELL LINE; CHEMOTAXIS; CHO CELLS; CRICETINAE; HUMANS; INDOLES; KINETICS; MODELS, MOLECULAR; MONOCYTES; MUTAGENESIS, SITE-DIRECTED; PIPERIDINES; RADIOLIGAND ASSAY; RECEPTORS, CHEMOKINE; RECOMBINANT PROTEINS; RHODOPSIN; STRUCTURAL HOMOLOGY, PROTEIN; TRANSFECTION;

EID: 0141678849     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm030862l     Document Type: Article

References (49)

1. Saunders: J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92.
2. Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert, C. A.; Horuk, R.; Matsushima, K.; Miller, L. H.; Oppenheim, J. J.; Power, C. A. International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors. Pharmacol. Rev. 2000, 52, 145-176.
3. Berkhout, T. A.; Sarau, H. M.; Moores, K.; White, J. R.; Elshourbagy, E. ; Apelbaum, E.; Makwana, J.; Foley, J. J.; Schmidt, D. B.; Imburgia, C.; McNulty, D.; Mathews, J.; O'Donnell, K.; O'Shannessy, D.; Scott, M.; Groot, P. H. E.; Macphee, C. Cloning, in Vitro Expression, and Functional Characterisation of a Novel Human CC Chemokine of the Monocyte Chemotactic Protein (MCP) Family (MCP-4) that Binds and Signals through the CC Chemokine Receptor 2B. J. Biol. Chem. 1997, 272, 16404-16413.
4. (a) Ross, R. Atherosclerosis-An Inflammatory Disease. New England J Med. 1999, 340, 115-126.
5. (b) Reape, T. J.; Groot, P. H. E.; Chemokines and Atherosclerosis. Atherosclerosis 1999, 147, 213-215.
6. (a) Yla-Herttuala, S.; Lipton, B. A.; Rosenfeld, M. E.; Sarkioja, T.; Yoshimura, T.; Leonard, E. J.; Witztum, J. L.; Steinberg, D. Expression of Monocyte Chemotactic Protein in Macrophage-rich Areas of Human and Rabbit Atherosclerotic Lesions. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 5252-5256.
7. (b) Takeya, M.; Yoshimura, T.; Leonard, E. J.; Takahashi, K. Detection of Monocyte Chemoattractant protein-1 in Human Atherosclerotic Lesions by an Anti-monocyte Chemoattractant Protein-1 Monoclonal Antibody. Hum. Pathol. 1993, 24, 534-539.
8. (c) Nelken, N. A.; Coughlin, S. R.; Gordon, D.; Wilcox, J. N. Monocyte Chemotactic Protein-1 in Human Atheromatous Plaques. J. Clin. Invest. 1991, 88, 1121-1127.
9. (d) Rayner, K.; Van Eersel, S.; Groot, P. H. E.; Reape, T. J. Localisation of mRNA for JE/MCP-1 and its Receptor CCR2 in Atherosclerotic Lesions of the ApoE Knockout Mouse. J. Vasc. Res. 2000, 37, 93-102.
10. (a) Gu, L.; Okada, Y.; Clinton, S. K.; Gerard, C.; Sukhova, G. K.; Libby, P.; Rollins, B. J. Absence of Monocyte Chemotactic Protein-1 Reduces Atherosclerosis in Low-Density Lipoprotein-deficient Mice. Mol. Cell. 1998, 2, 275-281.
11. (b) Boring, L.; Gosling, J.; Cleary, M.; Charo, I. F. Decreased Lesion Formation in CCR2-/- Mice Reveals a Role for Chemokines in the Initiation of Atherosclerosis. Nature 1998, 394, 894-897.
12. Aiello, R. J.; Bourassa, P.-A. K.; Lindsey, S.; Weng, W.; Natoli, E.; Rollins, B. J.; Milos, P. M. Monocyte Chemoattractant Protein-1 Accelerates Atherosclerosis in Apolipoprotein E-deficient Mice. Arteriosclerosis 1999, 19, 1518-1525.
13. Gong, J.-H.; Ratkay, L. G.; Waterfield, J. D.; Clark-Lewis, I. An Antagonist of Monocyte Chemoattractant Protein-1 (MCP-1) Inhibits Arthritis in the MRL-lpr Mouse Model. J. Exp. Med. 1997, 186, 131-137.
14. Trivedi, B. K.; Low, J. E.; Carson, K.; LaRosa, G. J. Chemokines: Targets for Novel Therapeutics. In Annual Reports in Medicinal Chemistry Doherty, A. M., Ed.; Academic Press: New York, 2000; Vol. 35, pp 191-200.
15. Forbes, I. T.; Cooper, D. G.; Dodds, E. K.; Hickey, D. M. B.; Ife, R. J. ; Meeson, M.; Berkhout, T.; Gohil, J.; Moores, K. CCR2B Receptor Antagonists: Conversion of a Weak HTS Hit to a Potent Lead Compound. Bioorg. Med. Chem. Lett. 2000, 10, 1803-1806.
16. Mirzadegan, T.; Diehl, F.; Ebi, B.; Bhakta, S.; Polsky, I.; McCarley, D. ; Mulkins, M.; Weatherhead, G. S.; Lapierre, J.-M.; Dankwardt, J.; Morgans, D.; Wilhelm, R.; Jarnagin, K. Identification of the Binding Site for a Novel Class of CCR2B Chemokine Receptor Antagonists. J. Biol. Chem. 2000, 275, 25562-25571.
17. (a) Shiraishi, M.; Kitayoshi, T.; Aramaki, Y.; Honda, S. WO Patent 99/32468.
18. (b) Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.; Okonogi, K.; Ogawa, Y.; Meguro, K.; Fujino, M. A Small Molecule Non-peptide CCR5 Antagonist with Highly Potent and Selective Anti-HIV Activity. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5698-5703.
19. (c) Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; sawada, H.; Nishimura, O.; Baba, M.; Fujino, M. Discovery of Novel, Potent, and Selective Small-molecule CCR5 Antagonists as Anti-HIV Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety. J. Med. Chem. 2000, 43, 2049-2063.
20. (a) Shiota, T. WO Patent 99/25686.
21. (b) Tarby, C. M.; Endo, N.; Moree, W.; Kataioka, K.; Ramirez-Weinhouse, M. M.; Imai, M.; Bradley, E.; Saunders, J.; Kato, Y.; Meyers, P. In 218th National ACS Meeting in New Orleans, 1999, Poster Abstract No. 82.
22. Shigenaga, S.; Manabe, T.; Matsuda, H.; Fujii, T.; Hiroi, J. Synthesis and Pharmacological Properties of N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2-thiazolyl]alkanesulfonamides as Novel Antiallergic Agents. Chem. Pharm. Bull. 1993, 41, 1589-1595.
23. b's is valid
24. (a) Unger, V. M.; Hargrave, P. A.; Baldwin, J. M.; Schertler, G. F. X. Arrangement of rhodopsin transmembrane α-helixes. Nature (London) 1997, 389, 203-206.
25. (b) Baldwin, J. M.; Schertler, G. F. X.; Unger, V. M. An alpha-carbon template for the transmembrane helixes in the rhodopsin family of G-protein-coupled receptors. J. Mol. Biol. 1997, 272, 144-164.
26. Blaney, F. E.; Raveglia, Luca, F.; Artico, M.; Cavagnera, S.; Dartois, C.; Farina, C.; Grugni, M.; Gagliardi, S.; Luttmann, M. A.; Martinelli, M.; Nadler, G. M. M. G.; Parini, C.; Petrillo, P.; Sarau, H. M.; Scheideler, M. A.; Hay, D. W. P.; Giardina, G. A. M. Stepwise Modulation of Neurokinin-3 and Neurokinin-2 Receptor Affinity and Selectivity in Quinoline Tachykinin Receptor Antagonists. J. Med. Chem. 2001, 44, 1675-1689.
27. Blaney, F. E.; Tennant, M. Computational tools and results in the construction of G protein-coupled receptor models. In Membrane Protein Models; Findlay, J. B. C., Ed.; Oxford, Bios Scientific Publishers Ltd., 1996; pp 161-176.
28. Blaney, J. M.; Crippen, G. M.; Dearing, A.; Dixon, J. S.; Spellmeyer, D. C. DGEOM95. Available from the Quantum Chemistry Program Exchange, Bloomington, IN, 1995.
29. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 1983, 4, 187-217. CHARMM, Version 25.2, Revision 98.0731; Accelrys Inc.: San Diego, CA, 1999.
30. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 1983, 4, 187-217. CHARMm, Version 25.2, Revision 98.0731; Accelrys Inc.: San Diego, CA, 1999.
31. (a) Elber, R.; Karplus, M. Enhanced sampling in molecular dynamics: Use of the time-dependent Hartree approximation for a simulation of carbon monoxide diffusion through myoglobin. J. Am. Chem. Soc. 1990, 112, 9161-75.
32. (b) Roitberg, A.; Elber, R. Modeling side chains in peptides and proteins: Application of the locally enhanced sampling and the simulated annealing methods to find minimum energy conformations. J. Chem. Phys. 1991, 95, 9277-87.
33. SPARTAN SGI, version 5.1.3; Wave function Inc., 18401 Von Karman, Suite 370, Irvine, CA 92612, 1999.
34. Clark, T.; Alex, A.; Beck, B.; Chandrasekhar, J.; Gedeck, P.; Horn, A.; Hutter, M.; Rauhut, G.; Sauer, W.; Steinke, T. Vamp 7.0; Oxford Molecular Ltd., 1998.
35. Catalyst, v4.7 (579); Accelrys Inc.: San Diego, CA, 2002.
36. Dunbrack, R. L., Jr.; Karplus, M. Backbone-dependent rotamer library for proteins. Application to side-chain prediction. J. Mol. Biol. 1993, 230, 543-74.
37. Polczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science (Washington, D. C.) 2000, 289, 739-745.
38. (a) Bromidge, S. M.; Dabbs, S.; Davies, D. T.; Davies, S.; Duckworth, D. M.; Forbes, I. T.; Gaster, L. M.; Ham, P.; Jones, G. E.; King, F. D.; Mulholland, K. R.; Saunders, D. V.; Wyman, P. A.; Blaney, F. E.; Clarke, S. E.; Blackburn, T. P.; Holland, V.; Kennett, G. A.; Lightowler, S.; Middlemiss, D. N.; Trail, B.; Riley, G. J.; Wood, M. D. Biarylcarbamoylindolines Are Novel and Selective 5-HT2C Receptor Inverse Agonists: Identification of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl] -6-trifluoromethylindoline (SB-243213) as a Potential Antidepressant/Anxiolytic Agent. J. Med. Chem. 2000, 43, 1123-1134.
39. (b) Gaster, L. M.; Blaney, F. E.; Duckworth, D. M.; Ham, P.; Jenkins, S. ; Jennings, A. J.; Joiner, G. F.; King, F. D.; Mulholland, K. R.; Starr, S.; Wyman, P. A.; Hagan, J. J.; Hatcher, J.; Jones, B. J.; Middlemiss, D. N.; Price, G. W.; Riley, G.; Roberts, C.; Routledge, C.; Selkirk, J.; Slade, P. D. The Selective 5-HT1B Receptor Inverse Agonist 1′-Methyl-5-[[2′ -methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4′-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo. J. Med. Chem. 1998, 41, 1218-1235.
40. Quanta98, version 98.1111; Accelrys Inc.: San Diego, CA, 1999.
41. Ballesteros, J. A.; Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosci. 1994, 25, 366-428.
42. FlexX; Tripos, Inc., 1699 South Hanley Rd., St. Louis, MO.
43. Ewing, T. J. A.; Kuntz, I. D.. Critical evaluation of search algorithms for automated molecular docking and database screening. J. Comput. Chem. 1997, 18, 1175-1189.
44. GOLD; Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK.
45. Docklt; Metaphorics, LLC., 27401 Los Altos #360, Mission Viejo, CA, 92691.
46. ICM, v2.7; MolSoft, San Diego, CA, 1998.
47. FLO; Thistlesoft Inc., Morris Township, NJ.
48. Bikker, J. A.; Trumpp-Kallmeyer, S.; Humblet, C. G-Protein Coupled Receptors: Models, Mutagenesis, and Drug Design. J. Med. Chem. 1998, 41, 2911-2927.
49. Blaney, F. E.; et al. Manuscript in preparation.