Homology modeling of opioid receptor-ligand complexes using experimental constraints

Irina D Pogozheva; Magdalena J Przydzial; Henry I Mosberg

doi:10.1208/aapsj070243

. 2005 Oct 5;7(2):E434–E448. doi: 10.1208/aapsj070243

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Irina D Pogozheva ¹, Magdalena J Przydzial ¹, Henry I Mosberg ^1,^✉

PMCID: PMC2750980 PMID: 16353922

Abstract

Opioid receptors interact with a variety of ligands, including endogenous peptides, opiates, and thousands of synthetic compounds with different structural scaffolds. In the absence of experimental structures of opioid receptors, theoretical modeling remains an important tool for structurefunction analysis. The combination of experimental studies and modeling approaches allows development of realistic models of ligand-receptor complexes helpful for elucidation of the molecular determinants of ligand affinity and selectivity and for understanding mechanisms of functional agonism or antagonism. In this review we provide a brief critical assessment of the status of such theoretical modeling and describe some common problems and their possible solutions. Currently, there are no reliable theoretical methods to generate the models in a completely automatic fashion. Models of higher accuracy can be produced if homology modeling, based on the rhodopsin X-ray template, is supplemented by experimental structural constraints appropriate for the active orinactive receptor conformations, together with receptor-specific and ligand-specific interactions. The experimental constraints can be derived from mutagenesis and cross-linking studies, correlative replacements of ligand and receptor groups, and incorporation of metal binding sites between residues of receptors or receptors and ligands. This review focuses on the analysis of similarity and differences of the refined homology models of μ, δ, and κ-opioid receptors in active and inactive states, emphasizing the molecular details of interaction of the receptors with some representative peptide and nonpeptide ligands, underlying the multiple modes of binding of small opiates, and the differences in binding modes of agonists and antagonists, and of peptides and alkaloids.

Keywords: ligand docking, modeling, opioid receptors, opioid ligands, pharmacophore model

Full Text

The Full Text of this article is available as a PDF (484.8 KB).

References

1.Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol. 1995;15:615–635. doi: 10.1007/BF02071128. [DOI] [PubMed] [Google Scholar]
2.Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953–990. doi: 10.1146/annurev.biochem.73.011303.073940. [DOI] [PubMed] [Google Scholar]
3.Pasternak GW. Multiple opiate receptors: déjà vu all over again. Neuropharmacology. 2004;47:312–323. doi: 10.1016/j.neuropharm.2004.07.004. [DOI] [PubMed] [Google Scholar]
4.Vaccarino AL, Kastin AJ. Endogenous opiates: 2000. Peptides. 2001;22:2257–2328. doi: 10.1016/S0196-9781(01)00566-6. [DOI] [PubMed] [Google Scholar]
5.Hruby VJ, Agnes RS. Conformation-activity relationships of opioid peptides with selective activities at opioid receptors. Biopolymers. 1999;51:391–410. doi: 10.1002/(SICI)1097-0282(1999)51:6<391::AID-BIP3>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
6.Mansour A, Hoversten MT, Taylor LP, Watson SJ, Akil H. The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res. 1995;700:89–98. doi: 10.1016/0006-8993(95)00928-J. [DOI] [PubMed] [Google Scholar]
7.Mosberg HI, Hurst R, Hruby VJ, et al. Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity. Life Sci. 1983;32:2565–2569. doi: 10.1016/0024-3205(83)90239-4. [DOI] [PubMed] [Google Scholar]
8.Pelton JT, Gulya K, Hruby VJ, Duckles S, Yamamura HI. Somatostatin analogs with affinity for opiate receptors in rat brain binding assay. Peptides. 1985;6:159–163. doi: 10.1016/0196-9781(85)90026-9. [DOI] [PubMed] [Google Scholar]
9.Pelton JT, Kazmierski W, Gulya K, Yamamura HI, Hruby VJ. Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors. J Med Chem. 1986;29:2370–2375. doi: 10.1021/jm00161a037. [DOI] [PubMed] [Google Scholar]
10.Kawasaki AM, Knapp RJ, Walton A, et al. Syntheses, opioid binding affinities, and potencies of dynorphin A analogues substituted in positions 1, 6, 7, 8 and 10. Int J Pept Protein Res. 1993;42:411–419. doi: 10.1111/j.1399-3011.1993.tb00148.x. [DOI] [PubMed] [Google Scholar]
11.Meyer JP, Collins N, Lung FD, et al. Design, synthesis, and biological properties of highly potent cyclic dynorphin A analogues: analogues cyclized between positions 5 and 11. J Med Chem. 1994;37:3910–3917. doi: 10.1021/jm00049a010. [DOI] [PubMed] [Google Scholar]
12.Arttamangkul S, Murray TF, DeLander GE, Aldrich JV. Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 1. Conformational constraint in the “message” sequence. J Med Chem. 1995;38:2410–2417. doi: 10.1021/jm00013a016. [DOI] [PubMed] [Google Scholar]
13.Lung FD, Collins N, Stropova D, et al. Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH2. J Med Chem. 1996;39:1136–1141. doi: 10.1021/jm950369c. [DOI] [PubMed] [Google Scholar]
14.Eguchi M. Recent advances in selective opioid receptor agonists and antagonists. Med Res Rev. 2004;24:182–212. doi: 10.1002/med.10059. [DOI] [PubMed] [Google Scholar]
15.Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies. Trends Biochem Sci. 2001;26:318–324. doi: 10.1016/S0968-0004(01)01799-6. [DOI] [PubMed] [Google Scholar]
16.Li J, Edwards PC, Burghammer M, Villa C, Schertler GF. Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol. 2004;343:1409–1438. doi: 10.1016/j.jmb.2004.08.090. [DOI] [PubMed] [Google Scholar]
17.Flower DR. Modeling G-protein-coupled receptors for drug design. Biochim Biophys Acta. 1999;1422:207–234. doi: 10.1016/s0304-4157(99)00006-4. [DOI] [PubMed] [Google Scholar]
18.Flippen-Anderson JL, George C, Bertha CM, Rice KC. X-ray structure of potent opioid receptor ligands: etonitazene, cis-(+)-3-methylfentanyl, etorphine, diprenorphine, and buprenorphine. Heterocycles. 1994;39:751–766. [Google Scholar]
19.Urbanczyk-Lipkowska Z, Etter MC, Lipkowski AW, Portoghese PS. The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity. J Mol Struct. 1987;159:287–295. doi: 10.1016/0022-2860(87)80047-9. [DOI] [Google Scholar]
20.Griffin JF, Larson DL, Portoghese PS. Crystal structures of alpha-and beta-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of mu opioid receptors. J Med Chem. 1986;29:778–783. doi: 10.1021/jm00155a031. [DOI] [PubMed] [Google Scholar]
21.Calderon SN, Rice KC, Rothman RB, et al. Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands. J Med Chem. 1997;40:695–704. doi: 10.1021/jm960319n. [DOI] [PubMed] [Google Scholar]
22.Lavecchia A, Greco G, Novellino E, Vittorio F, Ronsisvalle G. Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations. J Med Chem. 2000;43:2124–2134. doi: 10.1021/jm991161k. [DOI] [PubMed] [Google Scholar]
23.Doi M, Ishida T, Inoue M. Conformational characteristics of opioid kappa-receptor agonist: crystal structure of (5S, 7S, 8S)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5] dec-8-yl]benzeneacetamide (U69,593), and conformational comparison with some kappa-agonists. Chem Pharm Bull (Tokyo) 1990;38:1815–1818. doi: 10.1248/cpb.38.1815. [DOI] [PubMed] [Google Scholar]
24.Subramanian G, Patrelini MG, Portoghese PS, Ferguson DM. Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor. J Med Chem. 2000;43:381–391. doi: 10.1021/jm9903702. [DOI] [PubMed] [Google Scholar]
25.Mosberg HI, Fowler CB. Development and validation of opioid ligand-receptor interaction models: the structural basis of mu vs delta selectivity. J Pept Res. 2002;60:329–335. doi: 10.1034/j.1399-3011.2002.21061.x. [DOI] [PubMed] [Google Scholar]
26.Przydzial MJ, Pogozheva ID, Andrews SM, et al. Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the κ-opioid receptor. J Pept Res. 2005;65:333–342. doi: 10.1111/j.1399-3011.2005.00220.x. [DOI] [PubMed] [Google Scholar]
27.Mosberg HI, Omnaas JR, Medzihradsky F, Smith CB. Cyclic, disulfide- and dithioether-containing opioid tetrapeptides: development of a ligand with high delta opioid receptor selectivity and affinity. Life Sci. 1988;43:1013–1020. doi: 10.1016/0024-3205(88)90547-4. [DOI] [PubMed] [Google Scholar]
28.Mosberg HI, Lomize AL, Wang C, et al. Development of a model for the δ-opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) J Med Chem. 1994;37:4371–4383. doi: 10.1021/jm00051a015. [DOI] [PubMed] [Google Scholar]
29.Mosberg HI, Omnaas JR, Lomize A, et al. Development of a model for the δ-opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic δ-receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) J Med Chem. 1994;37:4384–4391. doi: 10.1021/jm00051a016. [DOI] [PubMed] [Google Scholar]
30.Mosberg HI, Dua RK, Pogozheva ID, Lomize AL. Development of a model for the δ-opioid receptor pharmacophore. 4. Residue 3 dehydrophenyl-alanine analogs of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic sidechain. Biopolymers. 1996;39:287–296. doi: 10.1002/(SICI)1097-0282(199609)39:3<287::AID-BIP2>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
31.Lomize AL, Flippen-Anderson JL, George C, Mosberg HI. Conformational analysis of the δ receptor-selective, cyclic opioid peptide, Tyr-c[D-Cys-Phe-D-Pen]OH(JOM-13): comparison of X-ray crystallographic structures, molecular mechanics simulations and1H NMR data. J Am Chem Soc. 1994;116:429–436. doi: 10.1021/ja00081a001. [DOI] [Google Scholar]
32.Ho JC. Development of a Model for the δ-opioid Receptor Pharmacophore. Ann Arbor, MI: University of Michigan; 1997. [Google Scholar]
33.McFadyen IJ, Ho JC, Mosberg HI, Traynor JR. Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation. J Pept Res. 2000;55:255–261. doi: 10.1034/j.1399-3011.2000.00177.x. [DOI] [PubMed] [Google Scholar]
34.Fowler CB, Pogozheva ID, Lomize AL, LeVine H, Mosberg HI. Complex of an active μ-opioid receptor with cyclic peptide agonist modeled from experimental constraints. Biochemistry. 2004;43:15796–15810. doi: 10.1021/bi048413q. [DOI] [PubMed] [Google Scholar]
35.Mosberg HI. Complementarity of delta opioid ligand pharmacophore and receptor models. Biopolymers. 1999;51:426–439. doi: 10.1002/(SICI)1097-0282(1999)51:6<426::AID-BIP5>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
36.Law PY, Loh HH. Regulation of opioid receptor activities. J Pharmacol Exp Ther. 1999;289:607–624. [PubMed] [Google Scholar]
37.Chaturvedi K, Christoffers KH, Singh K, Howells RD. Structure and regulation of opioid receptors. Biopolymers. 2000;55:334–346. doi: 10.1002/1097-0282(2000)55:4<334::AID-BIP1006>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
38.Chavkin C, McLaughlin JP, Celver JP. Regulation of opioid receptor function by chronic agonist exposure: constitutive activity and desensitization. Mol Pharmacol. 2001;60:20–25. doi: 10.1124/mol.60.1.20. [DOI] [PubMed] [Google Scholar]
39.Coward P, Wada HG, Falk MS, et al. Controlling signaling with a specifically designed Gi-coupled receptor. Proc Natl Acad Sci USA. 1998;95:352–357. doi: 10.1073/pnas.95.1.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Pogozheva ID, Lomize AL, Mosberg HI. Opioid receptor 3-dimensional structures from distance geometry calculations with hydrogen bonding constraints. Biophys J. 1998;75:612–634. doi: 10.1016/S0006-3495(98)77552-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Surratt CK, Johnson PS, Moriwaki A, et al. Mu opiate receptor: charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem. 1994;269:20548–20553. [PubMed] [Google Scholar]
42.Befort K, Tabbara L, Bausch S, Chavkin C, Evans C, Kieffer BL. The conserved aspartate residue in the third putative transmembrane domain of the delta-opioid receptor is not the anionic counterpart for cationic opiate binding but is a constituent of the receptor binding site. Mol Pharmacol. 1996;49:216–223. [PubMed] [Google Scholar]
43.Befort K, Tabbara L, Kling D, Maigret B, Kieffer BL. Role of aromatic transmembrane residues of the delta-opioid receptor in ligand recognition. J Biol Chem. 1996;271:10161–10168. doi: 10.1074/jbc.271.17.10161. [DOI] [PubMed] [Google Scholar]
44.Befort K, Zilliox C, Filliol D, Yue S, Kieffer BL. Constitutive activation of the delta opioid receptor by mutations in transmembrane domains III and VII. J Biol Chem. 1999;274:18574–18581. doi: 10.1074/jbc.274.26.18574. [DOI] [PubMed] [Google Scholar]
45.Bot G, Blake AD, Li S, Reisine T. Mutagenesis of the mouse delta opioid receptor converts(-)-buprenorphine from a partial agonist to an antagonist. J Pharmacol Exp Ther. 1998;284:283–290. [PubMed] [Google Scholar]
46.Bot G, Blake AD, Li S, Reisine T. Mutagenesis of a single amino acid in the rat mu-opioid receptor discriminates ligand binding. J Neurochem. 1998;70:358–365. doi: 10.1046/j.1471-4159.1998.70010358.x. [DOI] [PubMed] [Google Scholar]
47.Spivak CE, Beglan CL, Seidleck BK, et al. Naloxone activation of mu-opioid receptors mutated at a histidine residue lining the opioid binding cavity. Mol Pharmacol. 1997;52:983–992. doi: 10.1124/mol.52.6.983. [DOI] [PubMed] [Google Scholar]
48.Mansour A, Taylor LP, Fine JL, et al. Key residues defining the mu-opioid receptor binding pocket: a site-directed mutagenesis study. J Neurochem. 1997;68:344–353. doi: 10.1046/j.1471-4159.1997.68010344.x. [DOI] [PubMed] [Google Scholar]
49.Meng F, Ueda Y, Hoversten MT, et al. Creating a functional opioid alkaloid binding site in the orphanin FQ receptor through site-directed mutagenesis. Mol Pharmacol. 1998;53:772–777. doi: 10.1124/mol.53.4.772. [DOI] [PubMed] [Google Scholar]
50.Li JG, Chen C, Yin J, et al. ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion-pairing with morphine and naltrexone. Life Sci. 1999;65:175–185. doi: 10.1016/S0024-3205(99)00234-9. [DOI] [PubMed] [Google Scholar]
51.Fukuda K, Terasako K, Kato S, Mori K. Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the delta-and mu-opioid receptors. FEBS Lett. 1995;373:177–181. doi: 10.1016/0014-5793(95)01034-C. [DOI] [PubMed] [Google Scholar]
52.Minami M, Onogi T, Nakagawa T, et al. DAMGO, a mu-opioid receptor selective ligand, distinguishes between mu-and kappa-opioid receptors at a different region from that for the distinction between mu-and delta-opioid receptors. FEBS Lett. 1995;364:23–27. doi: 10.1016/0014-5793(95)00340-F. [DOI] [PubMed] [Google Scholar]
53.Wang JB, Johnson PS, Wu JM, Wang WF, Uhl GR. Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras. J Biol Chem. 1994;269:2966–25969. [PubMed] [Google Scholar]
54.Xue JC, Chen C, Zhu J, et al. Differential binding domains of peptide and non-peptide ligands in the cloned rat kappa opioid receptor. J Biol Chem. 1994;269:30195–30199. [PubMed] [Google Scholar]
55.Ferguson DM, Kramer S, Metzger TG, Law PY, Portoghese PS. Isosteric replacement of acidic with neutral residues in extracellular loop-2 of the kappa-opioid receptor does not affect dynorphin A(1–13) affinity and function. J Med Chem. 2000;43:1251–1252. doi: 10.1021/jm990583r. [DOI] [PubMed] [Google Scholar]
56.Bonner G, Meng F, Akil H. Selectivity of mu-opioid receptor determined by interfacial residues near third extracellular loop. Eur J Pharmacol. 2000;403:37–44. doi: 10.1016/S0014-2999(00)00578-1. [DOI] [PubMed] [Google Scholar]
57.Xu H, Lu YF, Partilla JS, et al. Opioid peptide receptor studies. 11. Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands. Synapse. 1999;32:23–28. doi: 10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
58.Ulens C, Boven M, Daenens P, Tytgat J. Interaction of p-fluoro fentanyl on cloned human opioid receptors and exploration of the role of Trp-318 and His-319 in mu-opioid receptor selectivity. J Pharmacol Exp Ther. 2000;294:1024–1033. [PubMed] [Google Scholar]
59.Pepin MC, Yue SY, Roberts E, Wahlestedt C, Walker P. Novel “restoration of function” mutagenesis strategy to identify amino acids of the delta-opioid receptor involved in ligand binding. J Biol Chem. 1997;272:9260–9267. doi: 10.1074/jbc.272.14.9260. [DOI] [PubMed] [Google Scholar]
60.Valiquette M, Vu HK, Yue SY, Wahlestedt C, Walker P. Involvement of Trp-284, Val-296, and Val-297 of the human delta-opioid receptor in binding of delta-selective ligands. J Biol Chem. 1996;271:18789–18796. doi: 10.1074/jbc.271.31.18789. [DOI] [PubMed] [Google Scholar]
61.Hjorth SA, Thirstrup K, Grandy DK, Schwartz TW. Analysis of selective binding epitopes for the kappa-opioid receptor antagonist norbinaltorphime. Mol Pharmacol. 1995;47:1089–1094. [PubMed] [Google Scholar]
62.Cavalli A, Babey AM, Loh HH. Altered adenylyl cyclase responsiveness subsequent to point mutations of Asp 128 in the third transmembrane domain of the delta-opioid receptor. Neuroscience. 1999;93:1025–1031. doi: 10.1016/S0306-4522(99)00280-8. [DOI] [PubMed] [Google Scholar]
63.Li J, Huang P, Chen C, Riel JK, Weinstein H, Liu-Chen LY. Constitutive activation of the mu opioid receptor by mutation of D3.49(164), but not D3.32(147): D3.49(164) is critical for stabilization of the inactive form of the receptor and for its expression. Biochemistry. 2001;40:12039–12050. doi: 10.1021/bi0100945. [DOI] [PubMed] [Google Scholar]
64.Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC. Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORLI receptor transmembrane-binding domain. Mol Pharmacol. 2000;57:495–502. doi: 10.1124/mol.57.3.495. [DOI] [PubMed] [Google Scholar]
65.DeCaillot FM, Befort K, Filliol D, Yue S, Walker P, Kieffer BL. Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation. Nat Struct Biol. 2003;10:629–636. doi: 10.1038/nsb950. [DOI] [PubMed] [Google Scholar]
66.Spivak CE, Beglan CL, Zollner C, Surratt CK. Beta-Funaltrexamine, a gauge for the recognition site of wildtype and mutant H297Q mu-opioid receptors. Synapse. 2003;49:55–60. doi: 10.1002/syn.10205. [DOI] [PubMed] [Google Scholar]
67.Chen C, Yin J, Riel JK, et al. Determination of the amino acid residue involved in [3H]beta-funaltrexamine covalent binding in the cloned rat mu-opioid receptor. J Biol Chem. 1996;271:21422–21429. doi: 10.1074/jbc.271.35.21422. [DOI] [PubMed] [Google Scholar]
68.Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Mutational evidence for a common kappa antagonist binding pocket in the wild-type kappa and mutant mu[K303E] opioid receptors. J Med Chem. 1998;41:4911–4914. doi: 10.1021/jm9805182. [DOI] [PubMed] [Google Scholar]
69.Larson DL, Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and kappa opioid receptors: molecular recognition loci for the pharmacophore and address components of kappa antagonists. J Med Chem. 2000;43:1573–1576. doi: 10.1021/jm000059g. [DOI] [PubMed] [Google Scholar]
70.Fowler CB, Pogozheva ID, LeVine H, Mosberg HI. Refinement of a homology model of the μ-opiodd receptor using distance constraints from intrinsic and engineered zinc-binding sites. Biochemistry. 2004;43:8700–8710. doi: 10.1021/bi036067r. [DOI] [PubMed] [Google Scholar]
71.Metzger TG, Paterlini MG, Portoghese PS, Ferguson DM. An analysis of the conserved residues between halobacterial retinal proteins and G-protein coupled receptors: implications for GPCR modeling. J Chem Inf Comput Sci. 1996;36:857–861. doi: 10.1021/ci950360j. [DOI] [PubMed] [Google Scholar]
72.Strahs D, Weinstein H. Comparative modeling and molecular dynamics studies of the delta, kappa and mu opioid receptors. Protein Eng. 1997;10:1019–1038. doi: 10.1093/protein/10.9.1019. [DOI] [PubMed] [Google Scholar]
73.Alkorta I, Loew GH. A 3D model of the delta opioid receptor and ligand-receptor complexes. Protein Eng. 1996;9:573–583. doi: 10.1093/protein/9.7.573. [DOI] [PubMed] [Google Scholar]
74.Subramanian G, Paterlini MG, Larson DL, Portoghese PS, Ferguson DM. Conformational analysis and automated receptor docking of selective arylacetamide-based kappa-opioid agonists. J Med Chem. 1998;41:4777–4789. doi: 10.1021/jm9803166. [DOI] [PubMed] [Google Scholar]
75.Paterlini G, Portoghese PS, Ferguson DM. Molecular simulation of dynorphin A-(1–10) binding to extracellular loop 2 of the kappa-opioid receptor: a model for receptor activation. J Med Chem. 1997;40:3254–3262. doi: 10.1021/jm970252j. [DOI] [PubMed] [Google Scholar]
76.Filizola M, Caakkonen L, Loew GH. 3D modeling, ligand binding and activations studies of the cloned mouse delta, mu, and kappa opioid receptors. Protein Eng. 1999;12:927–942. doi: 10.1093/protein/12.11.927. [DOI] [PubMed] [Google Scholar]
77.Filizola M, Carteni-Farina M, Perez JJ. Molecular modeling study of the differential ligand-receptor interaction at the mu, delta and kappa opioid receptors. J Comput Aided Mol Des. 1999;13:397–407. doi: 10.1023/A:1008079823736. [DOI] [PubMed] [Google Scholar]
78.Pogozheva ID, Lomize AL, Mosberg HI. The transmembrane 7 alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints. Biophys J. 1997;72:1963–1985. doi: 10.1016/S0006-3495(97)78842-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Lomize AL, Pogozheva ID, Mosberg HI. Structural organization of G-protein-coupled receptors. J Comput Aided Mol Des. 1999;13:325–353. doi: 10.1023/A:1008050821744. [DOI] [PubMed] [Google Scholar]
80.Vaidehi N, Floriano WB, Trabanino R, et al. Prediction of structure and function of G protein-coupled receptors. Proc Natl Acad Sci USA. 2002;99:12622–12627. doi: 10.1073/pnas.122357199. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Shacham S, Topf M, Avisar N, et al. Modeling the 3D structure of GPCRs from sequence. Med Res Rev. 2001;21:472–483. doi: 10.1002/med.1019. [DOI] [PubMed] [Google Scholar]
82.Shi L, Javitch JA. The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. Annu Rev Pharmacol Toxicol. 2002;42:437–467. doi: 10.1146/annurev.pharmtox.42.091101.144224. [DOI] [PubMed] [Google Scholar]
83.Lawson Z, Wheatley M. The third extracellular loop of G-protein-coupled receptors: more than just a linker between 2 important transmembrane helices. Biochem Soc Trans. 2004;32:1048–1050. doi: 10.1042/BST0321048. [DOI] [PubMed] [Google Scholar]
84.Baker D, Sali A. Protein structure prediction and structural genomics. Science. 2001;294:93–96. doi: 10.1126/science.1065659. [DOI] [PubMed] [Google Scholar]
85.Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science. 2000;289:739–745. doi: 10.1126/science.289.5480.739. [DOI] [PubMed] [Google Scholar]
86.Ballesteros JA, Shi L, Javitch JA. Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol Pharmacol. 2001;60:1–19. [PubMed] [Google Scholar]
87.Klabunde T, Hessler G. Drug design strategies for targeting G-protein-coupled receptors. ChemBioChem. 2002;3:928–944. doi: 10.1002/1439-7633(20021004)3:10<928::AID-CBIC928>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
88.Bissantz C, Bernard P, Hibert M, Rognan D. Protein-based virtual screening of chemical databases. II. Are homology models of G-protein coupled receptors suitable targets? Proteins. 2003;50:5–25. doi: 10.1002/prot.10237. [DOI] [PubMed] [Google Scholar]
89.Evers A, Klebe G. Ligand-supported homology modeling of g-protein-coupled receptor sites: models sufficient for successful virtual screening. Angew Chem Int Ed Engl. 2004;43:248–251. doi: 10.1002/anie.200352776. [DOI] [PubMed] [Google Scholar]
90.Horn F, Bettler E, Oliveira L, Campagne F, Cohen FE, Vriend G. GPCRDB information system for G protein-coupled receptors. Nucleic Acids Res. 2003;31:294–297. doi: 10.1093/nar/gkg103. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Huang P, Li J, Chen C, Visiers I, Weinstein H, Liu-Chen LY. Functional role of a conserved motif in TM6 of the rat mu opioid receptor: constitutively active and inactive receptors result from substitutions of Thr6.34(279) with Lys and Asp. Biochemistry. 2001;40:13501–13509. doi: 10.1021/bi010917q. [DOI] [PubMed] [Google Scholar]
92.Sali A, Blundell TL. Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol. 1993;234:779–815. doi: 10.1006/jmbi.1993.1626. [DOI] [PubMed] [Google Scholar]
93.Fiser A, Sali A. Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol. 2003;374:461–491. doi: 10.1016/S0076-6879(03)74020-8. [DOI] [PubMed] [Google Scholar]
94.Peitsch MC. ProMod and Swiss-Model: internet-based tools for automated comparative protein modelling. Biochem Soc Trans. 1996;24:274–279. doi: 10.1042/bst0240274. [DOI] [PubMed] [Google Scholar]
95.Lund O, Frimand K, Gorodkin J, et al. Protein distance constraints predicted by neural networks and probability density functions. Protein Eng. 1997;10:1241–1248. doi: 10.1093/protein/10.11.1241. [DOI] [PubMed] [Google Scholar]
96.Shindyalov IN, Bourne PE. Improving alignments in HM protocol with intermediate sequences. In: Forth Meeting on the Critical Assessment of Techniques for Protein Structure Prediction; 2000:A-92.
97.Lambert C, Leonard N, Bolle X, Depiereux E. ESyPred3D: prediction of proteins 3D structures. Bioinformatics. 2002;18:1250–1256. doi: 10.1093/bioinformatics/18.9.1250. [DOI] [PubMed] [Google Scholar]
98.Kim DE, Chivian D, Baker D. Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res. 2004;32:W526–W531. doi: 10.1093/nar/gkh468. [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Pieper U, Eswar N, Braberg H, et al. MODBASE, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res. 2004;32:D217–D222. doi: 10.1093/nar/gkh095. [DOI] [PMC free article] [PubMed] [Google Scholar]
100.Eswar N, John B, Mirkovic N, et al. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 2003;31:3375–3380. doi: 10.1093/nar/gkg543. [DOI] [PMC free article] [PubMed] [Google Scholar]
101.John B, Sali A. Comparative protein structure modeling by iterative alignment, model building and model assessment. Nucleic Acids Res. 2003;31:3982–3992. doi: 10.1093/nar/gkg460. [DOI] [PMC free article] [PubMed] [Google Scholar]
102.Riek RP, Rigoutsos I, Novotny J, Graham RM. Non-alpha-helical elements modulate polytopic membrane protein architecture. J Mol Biol. 2001;306:349–362. doi: 10.1006/jmbi.2000.4402. [DOI] [PubMed] [Google Scholar]
103.Fiser A, Do RK, Sali A. Modeling of loops in protein structures. Protein Sci. 2000;9:1753–1773. doi: 10.1110/ps.9.9.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Chothia C, Lesk AM. Helix movements and the reconstruction of the haem pocket during the evolution of the cytochrome c family. J Mol Biol. 1985;182:151–158. doi: 10.1016/0022-2836(85)90033-6. [DOI] [PubMed] [Google Scholar]
105.Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us? Trends Pharmacol Sci. 2001;22:587–593. doi: 10.1016/S0165-6147(00)01825-3. [DOI] [PubMed] [Google Scholar]
106.Karnik SS, Gogonea C, Patil S, Saad Y, Takezako T. Activation of G-protein-coupled receptors: a common molecular mechanism. Trends Endocrinol Metab. 2003;14:431–437. doi: 10.1016/j.tem.2003.09.007. [DOI] [PubMed] [Google Scholar]
107.Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor. Proc Natl Acad Sci USA. 2001;98:5997–6002. doi: 10.1073/pnas.101126198. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science. 1996;274:768–770. doi: 10.1126/science.274.5288.768. [DOI] [PubMed] [Google Scholar]
109.Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J. 1997;16:6737–6747. doi: 10.1093/emboj/16.22.6737. [DOI] [PMC free article] [PubMed] [Google Scholar]
110.Dunham TD, Farrens DL. Conformational changes in rhodopsin: movement of helix F detected by site-specific chemical labeling and fluorescence spectroscopy. J Biol Chem. 1999;274:1683–1690. doi: 10.1074/jbc.274.3.1683. [DOI] [PubMed] [Google Scholar]
111.Han M, Smith SO, Sakmar TP. Constitutive activation of opsin by mutation of methionine 257 on transmembrane helix 6. Biochemistry. 1998;37:8253–8261. doi: 10.1021/bi980147r. [DOI] [PubMed] [Google Scholar]
112.Cai K, Klein-Seetharaman J, Hwa J, Hubbell WL, Khorana HG. Structure and function in rhodopsin: effects of disulfide cross-links in the cytoplasmic face of rhodopsin on transducin activation and phosphorylation by rhodopsin kinase. Biochemistry. 1999;38:12893–12898. doi: 10.1021/bi9912443. [DOI] [PubMed] [Google Scholar]
113.Ghanouni P, Gryczynski Z, Steenhuis JJ, et al. Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J Biol Chem. 2001;276:24433–24436. doi: 10.1074/jbc.C100162200. [DOI] [PubMed] [Google Scholar]
114.Janz JM, Farrens DL. Rhodopsin activation exposes a key hydrophobic binding site for the transducin alpha-subunit C terminus. J Biol Chem. 2004;279:29767–29773. doi: 10.1074/jbc.M402567200. [DOI] [PubMed] [Google Scholar]
115.Hubbell WL, Altenbach C, Hubbell CM, Khorana HG. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide crosslinking. Adv Protein Chem. 2003;63:243–290. doi: 10.1016/S0065-3233(03)63010-X. [DOI] [PubMed] [Google Scholar]
116.Lin SW, Sakmar TP. Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state. Biochemistry. 1996;35:11149–11159. doi: 10.1021/bi960858u. [DOI] [PubMed] [Google Scholar]
117.Altenbach C, Cai K, Khorana HG, Hubbell WL. Structural features and light-dependent changes in the sequence 306–322 extending from helix VII to the palmitoylation sites in rhodopsin: a sitedrected spin-labeling study. Biochemistry. 1999;38:7931–7937. doi: 10.1021/bi9900121. [DOI] [PubMed] [Google Scholar]
118.Altenbach C, Klein-Seetharaman J, Hwa J, Khorana HG, Hubbell WL. Structural features and light-dependent changes in the sequence 59–75 connecting helices I and II in rhodopsin: a site-directed spinlabeling study. Biochemistry. 1999;38:7945–7949. doi: 10.1021/bi990014l. [DOI] [PubMed] [Google Scholar]
119.Altenbach C, Cai K, Klein-Seetharaman J, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 65 in helix TM1 and residues in the sequence 306–319 at the cytoplasmic end of helix TM7 and in helix H8. Biochemistry. 2001;40:15483–15492. doi: 10.1021/bi011546g. [DOI] [PubMed] [Google Scholar]
120.Altenbach C, Klein-Seetharaman J, Cai K, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 316 in helix 8 and residues in the sequence 60–75, covering the cytoplasmic end of helices TM1 and TM2 and their connection loop CL1. Biochemistry. 2001;40:15493–15500. doi: 10.1021/bi011545o. [DOI] [PubMed] [Google Scholar]
121.Gether U, Kobilka BK. G protein-coupled receptors. II. Mechanism of agonist activation. J Biol Chem. 1998;273:17979–17982. doi: 10.1074/jbc.273.29.17979. [DOI] [PubMed] [Google Scholar]
122.Devanathan S, Yao Z, Salamon Z, Kobilka B, Tollin G. Plasmon-waveguide resonance studies of ligand binding to the human beta 2-adrenergic receptor. Biochemistry. 2004;43:3280–3288. doi: 10.1021/bi035825a. [DOI] [PubMed] [Google Scholar]
123.Salamon Z, Cowell S, Varga E, Yamamura HI, Hruby VJ, Tollin G. Plasmon resonance studies of agonist/antagonist binding to the human delta-opioid receptor: new structural insights into receptor-ligand interactions. Biophys J. 2000;79:2463–2474. doi: 10.1016/S0006-3495(00)76489-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Salamon Z, Hruby VJ, Tollin G, Cowell S. Binding of agonists, antagonists and inverse agonists to the human delta-opioid receptor produces distinctly different conformational states distinguishable by plasmon-waveguide resonance spectroscopy. J Pept Res. 2002;60:322–328. doi: 10.1034/j.1399-3011.2002.21060.x. [DOI] [PubMed] [Google Scholar]
125.Alves ID, Ciano KA, Boguslavski V, et al. Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. J Biol Chem. 2004;279:44673–44682. doi: 10.1074/jbc.M404713200. [DOI] [PubMed] [Google Scholar]
126.Alves ID, Cowell SM, Salamon Z, Devanathan S, Tollin G, Hruby VJ. Different structural states of the proteolipid membrane are produced by ligand binding to the human delta-opioid receptor as shown by plasmon-waveguide resonance spectroscopy. Mol Pharmacol. 2004;65:1248–1257. doi: 10.1124/mol.65.5.1248. [DOI] [PubMed] [Google Scholar]
127.Tramontano A, Morea V. Exploiting evolutionary relationships for predicting protein structures. Biotechnol Bioeng. 2003;84:756–763. doi: 10.1002/bit.10850. [DOI] [PubMed] [Google Scholar]
128.Bates PA, Kelley LA, MacCallum RM, Sternberg MJ. Enhancement of protein modeling by human intervention in applying the automatic programs 3D-JIGSAW and 3D-PSSM.Proteins. 2001;39–46. [DOI] [PubMed]
129.Li X, Jacobson MP, Friesner RA. High-resolution prediction of protein helix positions and orientations. Proteins. 2004;55:368–382. doi: 10.1002/prot.20014. [DOI] [PubMed] [Google Scholar]
130.Evers A, Gohlke H, Klebe G. Ligand-supported homology modelling of protein binding-sites using knowledge-based potentials. J Mol Biol. 2003;334:327–345. doi: 10.1016/j.jmb.2003.09.032. [DOI] [PubMed] [Google Scholar]
131.Ward SD, Hamdan FF, Bloodworth LM, Wess J. Conformational changes that occur during M3 muscarinic acetylcholine receptor activation probed by the use of an in situ disulfide cross-linking strategy. J Biol Chem. 2002;277:2247–2257. doi: 10.1074/jbc.M107647200. [DOI] [PubMed] [Google Scholar]
132.Swaminath G, Lee TW, Kobilka B. Identification of an allosteric binding site for Zn2+ on the beta2 adrenergic receptor. J Biol Chem. 2003;278:352–356. doi: 10.1074/jbc.M206424200. [DOI] [PubMed] [Google Scholar]
133.Elling CE, Thirstrup K, Holst B, Schwartz TW. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor. Proc Natl Acad Sci USA. 1999;96:12322–12327. doi: 10.1073/pnas.96.22.12322. [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Holst B, Elling CE, Schwartz TW. Partial agonism through a zincion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor. Mol Pharmacol. 2000;58:263–270. doi: 10.1124/mol.58.2.263. [DOI] [PubMed] [Google Scholar]
135.Lagerstrom MC, Klovins J, Fredriksson R, et al. High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3. J Biol Chem. 2003;278:51521–51526. doi: 10.1074/jbc.M307683200. [DOI] [PubMed] [Google Scholar]
136.Ewing TJ, Makino S, Skillman AG, Kuntz ID. DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des. 2001;15:411–428. doi: 10.1023/A:1011115820450. [DOI] [PubMed] [Google Scholar]
137.Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997;267:727–748. doi: 10.1006/jmbi.1996.0897. [DOI] [PubMed] [Google Scholar]
138.Rarey M, Wefing S, Lengauer T. Placement of medium-sized molecular fragments into active sites of proteins. J Comput Aided Mol Des. 1996;10:41–54. doi: 10.1007/BF00124464. [DOI] [PubMed] [Google Scholar]
139.Taylor RD, Jewsbury PJ, Essex JW. FDS: flexible ligand and receptor docking with a continuum solvent model and soft-core energy function. J Comput Chem. 2003;24:1637–1656. doi: 10.1002/jcc.10295. [DOI] [PubMed] [Google Scholar]
140.Halgren TA, Murphy RB, Friesner RA, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47:1750–1759. doi: 10.1021/jm030644s. [DOI] [PubMed] [Google Scholar]
141.Venkatachalam CM, Jiang X, Oldfield T, Waldman M. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graph Model. 2003;21:289–307. doi: 10.1016/S1093-3263(02)00164-X. [DOI] [PubMed] [Google Scholar]
142.Cavasotto CN, Abagan RA. Protein flexibility in ligand docking and virtual screening to protein kinases. J Mol Biol. 2004;337:209–225. doi: 10.1016/j.jmb.2004.01.003. [DOI] [PubMed] [Google Scholar]
143.Perola E, Walters WP, Charifson PS. A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins. 2004;56:235–249. doi: 10.1002/prot.20088. [DOI] [PubMed] [Google Scholar]
144.Halperin I, Ma B, Wolfson H, Nussinov R. Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins. 2004;47:409–443. doi: 10.1002/prot.10115. [DOI] [PubMed] [Google Scholar]
145.Kontoyianni M, McClellan LM, Sokol GS. Evaluation of docking performance: comparative data on docking algorithms. J Med Chem. 2004;47:558–565. doi: 10.1021/jm0302997. [DOI] [PubMed] [Google Scholar]
146.Carlson HA, McCammon JA. Accommodating protein flexibility in computational drug design. Mol Pharmacol. 2000;57:213–218. [PubMed] [Google Scholar]
147.Evers A, Klebe G. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Chem. 2004;47:5381–5392. doi: 10.1021/jm0311487. [DOI] [PubMed] [Google Scholar]
148.Heyl DL, Mosberg HI. Modification of the Phe3 aromatic moiety in delta receptor-selective dermorphin/deltorphin-related tetrapeptides: effects on opioid receptor binding. Int J Pept Protein Res. 1992;39:450–457. doi: 10.1111/j.1399-3011.1992.tb01449.x. [DOI] [PubMed] [Google Scholar]
149.Sebastian A, Bidlack JM, Jiang Q, et al. 14 beta-[(p-nitrocinnamoy 1)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity. J Med Chem. 1993;36:3154–3160. doi: 10.1021/jm00073a015. [DOI] [PubMed] [Google Scholar]
150.Sagara T, Egashira H, Okamura M, Fujii I, Shimohigashi Y, Kanematsu K. Ligand recognition in mu opioid receptor: experimentally based modeling of mu opioid receptor binding sites and their testing by ligand docking. Bioorg Med Chem. 1996;4:2151–2166. doi: 10.1016/S0968-0896(96)00219-2. [DOI] [PubMed] [Google Scholar]
151.Chabre M, Breton J. Orientation of aromatic residues in rhodopsin: rotation of one tryptophan upon the meta I to meta II transition after illumination. Photochem Photobiol. 1979;30:295–299. doi: 10.1111/j.1751-1097.1979.tb07150.x. [DOI] [PubMed] [Google Scholar]
152.Baneres JL, Martin A, Hullot P, Girard JP, Rossi JC, Parello J. Structure-based analysis of GPCR function: conformational adaptation of both agonist and receptor upon leukotriene B4 binding to recombinant BLT1. J Mol Biol. 2003;329:801–814. doi: 10.1016/S0022-2836(03)00438-8. [DOI] [PubMed] [Google Scholar]
153.Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF. Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004;23:3609–3620. doi: 10.1038/sj.emboj.7600374. [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Sammes PG, Taylor JB. Opioid receptors. In: Hansch C, editor. Comprehensive Medicinal Chemistry. Oxford, UK: Pergamon Press; 1990. pp. 805–844. [Google Scholar]
155.Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Lu Y. Conversion of μ-, δ- and κ-receptor selective opioid peptide agonists into μ-, δ-, and κ-receptor selective antagonists. Life Sci. 2003;73:691–698. doi: 10.1016/S0024-3205(03)00389-8. [DOI] [PubMed] [Google Scholar]
156.Huang P, Kim S, Loew G. Development of a common 3D pharmacophore for delta-opioid recognition from peptides and non-peptides using a novel computer program. J Comput Aided Mol Des. 1997;11:21–28. doi: 10.1023/A:1008067209563. [DOI] [PubMed] [Google Scholar]
157.Filizola M, Villar HO, Loew GH. Molecular determinants of non-specific recognition of delta, mu, and kappa opioid receptors. Bioorg Med Chem. 2001;9:69–76. doi: 10.1016/S0968-0896(00)00223-6. [DOI] [PubMed] [Google Scholar]
158.Filizola M, Villar HO, Loew GH. Differentiation of delta, mu, and kappa opioid receptor agonists based on pharmacophore development and computed physicochemical properties. J Comput Aided Mol Des. 2001;15:297–307. doi: 10.1023/A:1011187320095. [DOI] [PubMed] [Google Scholar]
159.Bernard D, Coop A, MacKerell AD. 2D conformationally sampled pharmacophore: a ligand-based pharmacophore to differentiate delta opioid agonists from antagonists. J Am Chem Soc. 2003;125:3101–3107. doi: 10.1021/ja027644m. [DOI] [PubMed] [Google Scholar]

[CR1] 1.Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol. 1995;15:615–635. doi: 10.1007/BF02071128. [DOI] [PubMed] [Google Scholar]

[CR2] 2.Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953–990. doi: 10.1146/annurev.biochem.73.011303.073940. [DOI] [PubMed] [Google Scholar]

[CR3] 3.Pasternak GW. Multiple opiate receptors: déjà vu all over again. Neuropharmacology. 2004;47:312–323. doi: 10.1016/j.neuropharm.2004.07.004. [DOI] [PubMed] [Google Scholar]

[CR4] 4.Vaccarino AL, Kastin AJ. Endogenous opiates: 2000. Peptides. 2001;22:2257–2328. doi: 10.1016/S0196-9781(01)00566-6. [DOI] [PubMed] [Google Scholar]

[CR5] 5.Hruby VJ, Agnes RS. Conformation-activity relationships of opioid peptides with selective activities at opioid receptors. Biopolymers. 1999;51:391–410. doi: 10.1002/(SICI)1097-0282(1999)51:6<391::AID-BIP3>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]

[CR6] 6.Mansour A, Hoversten MT, Taylor LP, Watson SJ, Akil H. The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res. 1995;700:89–98. doi: 10.1016/0006-8993(95)00928-J. [DOI] [PubMed] [Google Scholar]

[CR7] 7.Mosberg HI, Hurst R, Hruby VJ, et al. Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity. Life Sci. 1983;32:2565–2569. doi: 10.1016/0024-3205(83)90239-4. [DOI] [PubMed] [Google Scholar]

[CR8] 8.Pelton JT, Gulya K, Hruby VJ, Duckles S, Yamamura HI. Somatostatin analogs with affinity for opiate receptors in rat brain binding assay. Peptides. 1985;6:159–163. doi: 10.1016/0196-9781(85)90026-9. [DOI] [PubMed] [Google Scholar]

[CR9] 9.Pelton JT, Kazmierski W, Gulya K, Yamamura HI, Hruby VJ. Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors. J Med Chem. 1986;29:2370–2375. doi: 10.1021/jm00161a037. [DOI] [PubMed] [Google Scholar]

[CR10] 10.Kawasaki AM, Knapp RJ, Walton A, et al. Syntheses, opioid binding affinities, and potencies of dynorphin A analogues substituted in positions 1, 6, 7, 8 and 10. Int J Pept Protein Res. 1993;42:411–419. doi: 10.1111/j.1399-3011.1993.tb00148.x. [DOI] [PubMed] [Google Scholar]

[CR11] 11.Meyer JP, Collins N, Lung FD, et al. Design, synthesis, and biological properties of highly potent cyclic dynorphin A analogues: analogues cyclized between positions 5 and 11. J Med Chem. 1994;37:3910–3917. doi: 10.1021/jm00049a010. [DOI] [PubMed] [Google Scholar]

[CR12] 12.Arttamangkul S, Murray TF, DeLander GE, Aldrich JV. Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 1. Conformational constraint in the “message” sequence. J Med Chem. 1995;38:2410–2417. doi: 10.1021/jm00013a016. [DOI] [PubMed] [Google Scholar]

[CR13] 13.Lung FD, Collins N, Stropova D, et al. Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH2. J Med Chem. 1996;39:1136–1141. doi: 10.1021/jm950369c. [DOI] [PubMed] [Google Scholar]

[CR14] 14.Eguchi M. Recent advances in selective opioid receptor agonists and antagonists. Med Res Rev. 2004;24:182–212. doi: 10.1002/med.10059. [DOI] [PubMed] [Google Scholar]

[CR15] 15.Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies. Trends Biochem Sci. 2001;26:318–324. doi: 10.1016/S0968-0004(01)01799-6. [DOI] [PubMed] [Google Scholar]

[CR16] 16.Li J, Edwards PC, Burghammer M, Villa C, Schertler GF. Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol. 2004;343:1409–1438. doi: 10.1016/j.jmb.2004.08.090. [DOI] [PubMed] [Google Scholar]

[CR17] 17.Flower DR. Modeling G-protein-coupled receptors for drug design. Biochim Biophys Acta. 1999;1422:207–234. doi: 10.1016/s0304-4157(99)00006-4. [DOI] [PubMed] [Google Scholar]

[CR18] 18.Flippen-Anderson JL, George C, Bertha CM, Rice KC. X-ray structure of potent opioid receptor ligands: etonitazene, cis-(+)-3-methylfentanyl, etorphine, diprenorphine, and buprenorphine. Heterocycles. 1994;39:751–766. [Google Scholar]

[CR19] 19.Urbanczyk-Lipkowska Z, Etter MC, Lipkowski AW, Portoghese PS. The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity. J Mol Struct. 1987;159:287–295. doi: 10.1016/0022-2860(87)80047-9. [DOI] [Google Scholar]

[CR20] 20.Griffin JF, Larson DL, Portoghese PS. Crystal structures of alpha-and beta-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of mu opioid receptors. J Med Chem. 1986;29:778–783. doi: 10.1021/jm00155a031. [DOI] [PubMed] [Google Scholar]

[CR21] 21.Calderon SN, Rice KC, Rothman RB, et al. Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands. J Med Chem. 1997;40:695–704. doi: 10.1021/jm960319n. [DOI] [PubMed] [Google Scholar]

[CR22] 22.Lavecchia A, Greco G, Novellino E, Vittorio F, Ronsisvalle G. Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations. J Med Chem. 2000;43:2124–2134. doi: 10.1021/jm991161k. [DOI] [PubMed] [Google Scholar]

[CR23] 23.Doi M, Ishida T, Inoue M. Conformational characteristics of opioid kappa-receptor agonist: crystal structure of (5S, 7S, 8S)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5] dec-8-yl]benzeneacetamide (U69,593), and conformational comparison with some kappa-agonists. Chem Pharm Bull (Tokyo) 1990;38:1815–1818. doi: 10.1248/cpb.38.1815. [DOI] [PubMed] [Google Scholar]

[CR24] 24.Subramanian G, Patrelini MG, Portoghese PS, Ferguson DM. Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor. J Med Chem. 2000;43:381–391. doi: 10.1021/jm9903702. [DOI] [PubMed] [Google Scholar]

[CR25] 25.Mosberg HI, Fowler CB. Development and validation of opioid ligand-receptor interaction models: the structural basis of mu vs delta selectivity. J Pept Res. 2002;60:329–335. doi: 10.1034/j.1399-3011.2002.21061.x. [DOI] [PubMed] [Google Scholar]

[CR26] 26.Przydzial MJ, Pogozheva ID, Andrews SM, et al. Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the κ-opioid receptor. J Pept Res. 2005;65:333–342. doi: 10.1111/j.1399-3011.2005.00220.x. [DOI] [PubMed] [Google Scholar]

[CR27] 27.Mosberg HI, Omnaas JR, Medzihradsky F, Smith CB. Cyclic, disulfide- and dithioether-containing opioid tetrapeptides: development of a ligand with high delta opioid receptor selectivity and affinity. Life Sci. 1988;43:1013–1020. doi: 10.1016/0024-3205(88)90547-4. [DOI] [PubMed] [Google Scholar]

[CR28] 28.Mosberg HI, Lomize AL, Wang C, et al. Development of a model for the δ-opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) J Med Chem. 1994;37:4371–4383. doi: 10.1021/jm00051a015. [DOI] [PubMed] [Google Scholar]

[CR29] 29.Mosberg HI, Omnaas JR, Lomize A, et al. Development of a model for the δ-opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic δ-receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) J Med Chem. 1994;37:4384–4391. doi: 10.1021/jm00051a016. [DOI] [PubMed] [Google Scholar]

[CR30] 30.Mosberg HI, Dua RK, Pogozheva ID, Lomize AL. Development of a model for the δ-opioid receptor pharmacophore. 4. Residue 3 dehydrophenyl-alanine analogs of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic sidechain. Biopolymers. 1996;39:287–296. doi: 10.1002/(SICI)1097-0282(199609)39:3<287::AID-BIP2>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]

[CR31] 31.Lomize AL, Flippen-Anderson JL, George C, Mosberg HI. Conformational analysis of the δ receptor-selective, cyclic opioid peptide, Tyr-c[D-Cys-Phe-D-Pen]OH(JOM-13): comparison of X-ray crystallographic structures, molecular mechanics simulations and1H NMR data. J Am Chem Soc. 1994;116:429–436. doi: 10.1021/ja00081a001. [DOI] [Google Scholar]

[CR32] 32.Ho JC. Development of a Model for the δ-opioid Receptor Pharmacophore. Ann Arbor, MI: University of Michigan; 1997. [Google Scholar]

[CR33] 33.McFadyen IJ, Ho JC, Mosberg HI, Traynor JR. Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation. J Pept Res. 2000;55:255–261. doi: 10.1034/j.1399-3011.2000.00177.x. [DOI] [PubMed] [Google Scholar]

[CR34] 34.Fowler CB, Pogozheva ID, Lomize AL, LeVine H, Mosberg HI. Complex of an active μ-opioid receptor with cyclic peptide agonist modeled from experimental constraints. Biochemistry. 2004;43:15796–15810. doi: 10.1021/bi048413q. [DOI] [PubMed] [Google Scholar]

[CR35] 35.Mosberg HI. Complementarity of delta opioid ligand pharmacophore and receptor models. Biopolymers. 1999;51:426–439. doi: 10.1002/(SICI)1097-0282(1999)51:6<426::AID-BIP5>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]

[CR36] 36.Law PY, Loh HH. Regulation of opioid receptor activities. J Pharmacol Exp Ther. 1999;289:607–624. [PubMed] [Google Scholar]

[CR37] 37.Chaturvedi K, Christoffers KH, Singh K, Howells RD. Structure and regulation of opioid receptors. Biopolymers. 2000;55:334–346. doi: 10.1002/1097-0282(2000)55:4<334::AID-BIP1006>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]

[CR38] 38.Chavkin C, McLaughlin JP, Celver JP. Regulation of opioid receptor function by chronic agonist exposure: constitutive activity and desensitization. Mol Pharmacol. 2001;60:20–25. doi: 10.1124/mol.60.1.20. [DOI] [PubMed] [Google Scholar]

[CR39] 39.Coward P, Wada HG, Falk MS, et al. Controlling signaling with a specifically designed Gi-coupled receptor. Proc Natl Acad Sci USA. 1998;95:352–357. doi: 10.1073/pnas.95.1.352. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR40] 40.Pogozheva ID, Lomize AL, Mosberg HI. Opioid receptor 3-dimensional structures from distance geometry calculations with hydrogen bonding constraints. Biophys J. 1998;75:612–634. doi: 10.1016/S0006-3495(98)77552-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR41] 41.Surratt CK, Johnson PS, Moriwaki A, et al. Mu opiate receptor: charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem. 1994;269:20548–20553. [PubMed] [Google Scholar]

[CR42] 42.Befort K, Tabbara L, Bausch S, Chavkin C, Evans C, Kieffer BL. The conserved aspartate residue in the third putative transmembrane domain of the delta-opioid receptor is not the anionic counterpart for cationic opiate binding but is a constituent of the receptor binding site. Mol Pharmacol. 1996;49:216–223. [PubMed] [Google Scholar]

[CR43] 43.Befort K, Tabbara L, Kling D, Maigret B, Kieffer BL. Role of aromatic transmembrane residues of the delta-opioid receptor in ligand recognition. J Biol Chem. 1996;271:10161–10168. doi: 10.1074/jbc.271.17.10161. [DOI] [PubMed] [Google Scholar]

[CR44] 44.Befort K, Zilliox C, Filliol D, Yue S, Kieffer BL. Constitutive activation of the delta opioid receptor by mutations in transmembrane domains III and VII. J Biol Chem. 1999;274:18574–18581. doi: 10.1074/jbc.274.26.18574. [DOI] [PubMed] [Google Scholar]

[CR45] 45.Bot G, Blake AD, Li S, Reisine T. Mutagenesis of the mouse delta opioid receptor converts(-)-buprenorphine from a partial agonist to an antagonist. J Pharmacol Exp Ther. 1998;284:283–290. [PubMed] [Google Scholar]

[CR46] 46.Bot G, Blake AD, Li S, Reisine T. Mutagenesis of a single amino acid in the rat mu-opioid receptor discriminates ligand binding. J Neurochem. 1998;70:358–365. doi: 10.1046/j.1471-4159.1998.70010358.x. [DOI] [PubMed] [Google Scholar]

[CR47] 47.Spivak CE, Beglan CL, Seidleck BK, et al. Naloxone activation of mu-opioid receptors mutated at a histidine residue lining the opioid binding cavity. Mol Pharmacol. 1997;52:983–992. doi: 10.1124/mol.52.6.983. [DOI] [PubMed] [Google Scholar]

[CR48] 48.Mansour A, Taylor LP, Fine JL, et al. Key residues defining the mu-opioid receptor binding pocket: a site-directed mutagenesis study. J Neurochem. 1997;68:344–353. doi: 10.1046/j.1471-4159.1997.68010344.x. [DOI] [PubMed] [Google Scholar]

[CR49] 49.Meng F, Ueda Y, Hoversten MT, et al. Creating a functional opioid alkaloid binding site in the orphanin FQ receptor through site-directed mutagenesis. Mol Pharmacol. 1998;53:772–777. doi: 10.1124/mol.53.4.772. [DOI] [PubMed] [Google Scholar]

[CR50] 50.Li JG, Chen C, Yin J, et al. ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion-pairing with morphine and naltrexone. Life Sci. 1999;65:175–185. doi: 10.1016/S0024-3205(99)00234-9. [DOI] [PubMed] [Google Scholar]

[CR51] 51.Fukuda K, Terasako K, Kato S, Mori K. Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the delta-and mu-opioid receptors. FEBS Lett. 1995;373:177–181. doi: 10.1016/0014-5793(95)01034-C. [DOI] [PubMed] [Google Scholar]

[CR52] 52.Minami M, Onogi T, Nakagawa T, et al. DAMGO, a mu-opioid receptor selective ligand, distinguishes between mu-and kappa-opioid receptors at a different region from that for the distinction between mu-and delta-opioid receptors. FEBS Lett. 1995;364:23–27. doi: 10.1016/0014-5793(95)00340-F. [DOI] [PubMed] [Google Scholar]

[CR53] 53.Wang JB, Johnson PS, Wu JM, Wang WF, Uhl GR. Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras. J Biol Chem. 1994;269:2966–25969. [PubMed] [Google Scholar]

[CR54] 54.Xue JC, Chen C, Zhu J, et al. Differential binding domains of peptide and non-peptide ligands in the cloned rat kappa opioid receptor. J Biol Chem. 1994;269:30195–30199. [PubMed] [Google Scholar]

[CR55] 55.Ferguson DM, Kramer S, Metzger TG, Law PY, Portoghese PS. Isosteric replacement of acidic with neutral residues in extracellular loop-2 of the kappa-opioid receptor does not affect dynorphin A(1–13) affinity and function. J Med Chem. 2000;43:1251–1252. doi: 10.1021/jm990583r. [DOI] [PubMed] [Google Scholar]

[CR56] 56.Bonner G, Meng F, Akil H. Selectivity of mu-opioid receptor determined by interfacial residues near third extracellular loop. Eur J Pharmacol. 2000;403:37–44. doi: 10.1016/S0014-2999(00)00578-1. [DOI] [PubMed] [Google Scholar]

[CR57] 57.Xu H, Lu YF, Partilla JS, et al. Opioid peptide receptor studies. 11. Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands. Synapse. 1999;32:23–28. doi: 10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]

[CR58] 58.Ulens C, Boven M, Daenens P, Tytgat J. Interaction of p-fluoro fentanyl on cloned human opioid receptors and exploration of the role of Trp-318 and His-319 in mu-opioid receptor selectivity. J Pharmacol Exp Ther. 2000;294:1024–1033. [PubMed] [Google Scholar]

[CR59] 59.Pepin MC, Yue SY, Roberts E, Wahlestedt C, Walker P. Novel “restoration of function” mutagenesis strategy to identify amino acids of the delta-opioid receptor involved in ligand binding. J Biol Chem. 1997;272:9260–9267. doi: 10.1074/jbc.272.14.9260. [DOI] [PubMed] [Google Scholar]

[CR60] 60.Valiquette M, Vu HK, Yue SY, Wahlestedt C, Walker P. Involvement of Trp-284, Val-296, and Val-297 of the human delta-opioid receptor in binding of delta-selective ligands. J Biol Chem. 1996;271:18789–18796. doi: 10.1074/jbc.271.31.18789. [DOI] [PubMed] [Google Scholar]

[CR61] 61.Hjorth SA, Thirstrup K, Grandy DK, Schwartz TW. Analysis of selective binding epitopes for the kappa-opioid receptor antagonist norbinaltorphime. Mol Pharmacol. 1995;47:1089–1094. [PubMed] [Google Scholar]

[CR62] 62.Cavalli A, Babey AM, Loh HH. Altered adenylyl cyclase responsiveness subsequent to point mutations of Asp 128 in the third transmembrane domain of the delta-opioid receptor. Neuroscience. 1999;93:1025–1031. doi: 10.1016/S0306-4522(99)00280-8. [DOI] [PubMed] [Google Scholar]

[CR63] 63.Li J, Huang P, Chen C, Riel JK, Weinstein H, Liu-Chen LY. Constitutive activation of the mu opioid receptor by mutation of D3.49(164), but not D3.32(147): D3.49(164) is critical for stabilization of the inactive form of the receptor and for its expression. Biochemistry. 2001;40:12039–12050. doi: 10.1021/bi0100945. [DOI] [PubMed] [Google Scholar]

[CR64] 64.Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC. Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORLI receptor transmembrane-binding domain. Mol Pharmacol. 2000;57:495–502. doi: 10.1124/mol.57.3.495. [DOI] [PubMed] [Google Scholar]

[CR65] 65.DeCaillot FM, Befort K, Filliol D, Yue S, Walker P, Kieffer BL. Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation. Nat Struct Biol. 2003;10:629–636. doi: 10.1038/nsb950. [DOI] [PubMed] [Google Scholar]

[CR66] 66.Spivak CE, Beglan CL, Zollner C, Surratt CK. Beta-Funaltrexamine, a gauge for the recognition site of wildtype and mutant H297Q mu-opioid receptors. Synapse. 2003;49:55–60. doi: 10.1002/syn.10205. [DOI] [PubMed] [Google Scholar]

[CR67] 67.Chen C, Yin J, Riel JK, et al. Determination of the amino acid residue involved in [3H]beta-funaltrexamine covalent binding in the cloned rat mu-opioid receptor. J Biol Chem. 1996;271:21422–21429. doi: 10.1074/jbc.271.35.21422. [DOI] [PubMed] [Google Scholar]

[CR68] 68.Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Mutational evidence for a common kappa antagonist binding pocket in the wild-type kappa and mutant mu[K303E] opioid receptors. J Med Chem. 1998;41:4911–4914. doi: 10.1021/jm9805182. [DOI] [PubMed] [Google Scholar]

[CR69] 69.Larson DL, Jones RM, Hjorth SA, Schwartz TW, Portoghese PS. Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and kappa opioid receptors: molecular recognition loci for the pharmacophore and address components of kappa antagonists. J Med Chem. 2000;43:1573–1576. doi: 10.1021/jm000059g. [DOI] [PubMed] [Google Scholar]

[CR70] 70.Fowler CB, Pogozheva ID, LeVine H, Mosberg HI. Refinement of a homology model of the μ-opiodd receptor using distance constraints from intrinsic and engineered zinc-binding sites. Biochemistry. 2004;43:8700–8710. doi: 10.1021/bi036067r. [DOI] [PubMed] [Google Scholar]

[CR71] 71.Metzger TG, Paterlini MG, Portoghese PS, Ferguson DM. An analysis of the conserved residues between halobacterial retinal proteins and G-protein coupled receptors: implications for GPCR modeling. J Chem Inf Comput Sci. 1996;36:857–861. doi: 10.1021/ci950360j. [DOI] [PubMed] [Google Scholar]

[CR72] 72.Strahs D, Weinstein H. Comparative modeling and molecular dynamics studies of the delta, kappa and mu opioid receptors. Protein Eng. 1997;10:1019–1038. doi: 10.1093/protein/10.9.1019. [DOI] [PubMed] [Google Scholar]

[CR73] 73.Alkorta I, Loew GH. A 3D model of the delta opioid receptor and ligand-receptor complexes. Protein Eng. 1996;9:573–583. doi: 10.1093/protein/9.7.573. [DOI] [PubMed] [Google Scholar]

[CR74] 74.Subramanian G, Paterlini MG, Larson DL, Portoghese PS, Ferguson DM. Conformational analysis and automated receptor docking of selective arylacetamide-based kappa-opioid agonists. J Med Chem. 1998;41:4777–4789. doi: 10.1021/jm9803166. [DOI] [PubMed] [Google Scholar]

[CR75] 75.Paterlini G, Portoghese PS, Ferguson DM. Molecular simulation of dynorphin A-(1–10) binding to extracellular loop 2 of the kappa-opioid receptor: a model for receptor activation. J Med Chem. 1997;40:3254–3262. doi: 10.1021/jm970252j. [DOI] [PubMed] [Google Scholar]

[CR76] 76.Filizola M, Caakkonen L, Loew GH. 3D modeling, ligand binding and activations studies of the cloned mouse delta, mu, and kappa opioid receptors. Protein Eng. 1999;12:927–942. doi: 10.1093/protein/12.11.927. [DOI] [PubMed] [Google Scholar]

[CR77] 77.Filizola M, Carteni-Farina M, Perez JJ. Molecular modeling study of the differential ligand-receptor interaction at the mu, delta and kappa opioid receptors. J Comput Aided Mol Des. 1999;13:397–407. doi: 10.1023/A:1008079823736. [DOI] [PubMed] [Google Scholar]

[CR78] 78.Pogozheva ID, Lomize AL, Mosberg HI. The transmembrane 7 alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints. Biophys J. 1997;72:1963–1985. doi: 10.1016/S0006-3495(97)78842-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR79] 79.Lomize AL, Pogozheva ID, Mosberg HI. Structural organization of G-protein-coupled receptors. J Comput Aided Mol Des. 1999;13:325–353. doi: 10.1023/A:1008050821744. [DOI] [PubMed] [Google Scholar]

[CR80] 80.Vaidehi N, Floriano WB, Trabanino R, et al. Prediction of structure and function of G protein-coupled receptors. Proc Natl Acad Sci USA. 2002;99:12622–12627. doi: 10.1073/pnas.122357199. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR81] 81.Shacham S, Topf M, Avisar N, et al. Modeling the 3D structure of GPCRs from sequence. Med Res Rev. 2001;21:472–483. doi: 10.1002/med.1019. [DOI] [PubMed] [Google Scholar]

[CR82] 82.Shi L, Javitch JA. The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. Annu Rev Pharmacol Toxicol. 2002;42:437–467. doi: 10.1146/annurev.pharmtox.42.091101.144224. [DOI] [PubMed] [Google Scholar]

[CR83] 83.Lawson Z, Wheatley M. The third extracellular loop of G-protein-coupled receptors: more than just a linker between 2 important transmembrane helices. Biochem Soc Trans. 2004;32:1048–1050. doi: 10.1042/BST0321048. [DOI] [PubMed] [Google Scholar]

[CR84] 84.Baker D, Sali A. Protein structure prediction and structural genomics. Science. 2001;294:93–96. doi: 10.1126/science.1065659. [DOI] [PubMed] [Google Scholar]

[CR85] 85.Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science. 2000;289:739–745. doi: 10.1126/science.289.5480.739. [DOI] [PubMed] [Google Scholar]

[CR86] 86.Ballesteros JA, Shi L, Javitch JA. Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol Pharmacol. 2001;60:1–19. [PubMed] [Google Scholar]

[CR87] 87.Klabunde T, Hessler G. Drug design strategies for targeting G-protein-coupled receptors. ChemBioChem. 2002;3:928–944. doi: 10.1002/1439-7633(20021004)3:10<928::AID-CBIC928>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]

[CR88] 88.Bissantz C, Bernard P, Hibert M, Rognan D. Protein-based virtual screening of chemical databases. II. Are homology models of G-protein coupled receptors suitable targets? Proteins. 2003;50:5–25. doi: 10.1002/prot.10237. [DOI] [PubMed] [Google Scholar]

[CR89] 89.Evers A, Klebe G. Ligand-supported homology modeling of g-protein-coupled receptor sites: models sufficient for successful virtual screening. Angew Chem Int Ed Engl. 2004;43:248–251. doi: 10.1002/anie.200352776. [DOI] [PubMed] [Google Scholar]

[CR90] 90.Horn F, Bettler E, Oliveira L, Campagne F, Cohen FE, Vriend G. GPCRDB information system for G protein-coupled receptors. Nucleic Acids Res. 2003;31:294–297. doi: 10.1093/nar/gkg103. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR91] 91.Huang P, Li J, Chen C, Visiers I, Weinstein H, Liu-Chen LY. Functional role of a conserved motif in TM6 of the rat mu opioid receptor: constitutively active and inactive receptors result from substitutions of Thr6.34(279) with Lys and Asp. Biochemistry. 2001;40:13501–13509. doi: 10.1021/bi010917q. [DOI] [PubMed] [Google Scholar]

[CR92] 92.Sali A, Blundell TL. Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol. 1993;234:779–815. doi: 10.1006/jmbi.1993.1626. [DOI] [PubMed] [Google Scholar]

[CR93] 93.Fiser A, Sali A. Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol. 2003;374:461–491. doi: 10.1016/S0076-6879(03)74020-8. [DOI] [PubMed] [Google Scholar]

[CR94] 94.Peitsch MC. ProMod and Swiss-Model: internet-based tools for automated comparative protein modelling. Biochem Soc Trans. 1996;24:274–279. doi: 10.1042/bst0240274. [DOI] [PubMed] [Google Scholar]

[CR95] 95.Lund O, Frimand K, Gorodkin J, et al. Protein distance constraints predicted by neural networks and probability density functions. Protein Eng. 1997;10:1241–1248. doi: 10.1093/protein/10.11.1241. [DOI] [PubMed] [Google Scholar]

[CR96] 96.Shindyalov IN, Bourne PE. Improving alignments in HM protocol with intermediate sequences. In: Forth Meeting on the Critical Assessment of Techniques for Protein Structure Prediction; 2000:A-92.

[CR97] 97.Lambert C, Leonard N, Bolle X, Depiereux E. ESyPred3D: prediction of proteins 3D structures. Bioinformatics. 2002;18:1250–1256. doi: 10.1093/bioinformatics/18.9.1250. [DOI] [PubMed] [Google Scholar]

[CR98] 98.Kim DE, Chivian D, Baker D. Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res. 2004;32:W526–W531. doi: 10.1093/nar/gkh468. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR99] 99.Pieper U, Eswar N, Braberg H, et al. MODBASE, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res. 2004;32:D217–D222. doi: 10.1093/nar/gkh095. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR100] 100.Eswar N, John B, Mirkovic N, et al. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 2003;31:3375–3380. doi: 10.1093/nar/gkg543. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR101] 101.John B, Sali A. Comparative protein structure modeling by iterative alignment, model building and model assessment. Nucleic Acids Res. 2003;31:3982–3992. doi: 10.1093/nar/gkg460. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR102] 102.Riek RP, Rigoutsos I, Novotny J, Graham RM. Non-alpha-helical elements modulate polytopic membrane protein architecture. J Mol Biol. 2001;306:349–362. doi: 10.1006/jmbi.2000.4402. [DOI] [PubMed] [Google Scholar]

[CR103] 103.Fiser A, Do RK, Sali A. Modeling of loops in protein structures. Protein Sci. 2000;9:1753–1773. doi: 10.1110/ps.9.9.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR104] 104.Chothia C, Lesk AM. Helix movements and the reconstruction of the haem pocket during the evolution of the cytochrome c family. J Mol Biol. 1985;182:151–158. doi: 10.1016/0022-2836(85)90033-6. [DOI] [PubMed] [Google Scholar]

[CR105] 105.Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us? Trends Pharmacol Sci. 2001;22:587–593. doi: 10.1016/S0165-6147(00)01825-3. [DOI] [PubMed] [Google Scholar]

[CR106] 106.Karnik SS, Gogonea C, Patil S, Saad Y, Takezako T. Activation of G-protein-coupled receptors: a common molecular mechanism. Trends Endocrinol Metab. 2003;14:431–437. doi: 10.1016/j.tem.2003.09.007. [DOI] [PubMed] [Google Scholar]

[CR107] 107.Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor. Proc Natl Acad Sci USA. 2001;98:5997–6002. doi: 10.1073/pnas.101126198. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR108] 108.Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science. 1996;274:768–770. doi: 10.1126/science.274.5288.768. [DOI] [PubMed] [Google Scholar]

[CR109] 109.Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J. 1997;16:6737–6747. doi: 10.1093/emboj/16.22.6737. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR110] 110.Dunham TD, Farrens DL. Conformational changes in rhodopsin: movement of helix F detected by site-specific chemical labeling and fluorescence spectroscopy. J Biol Chem. 1999;274:1683–1690. doi: 10.1074/jbc.274.3.1683. [DOI] [PubMed] [Google Scholar]

[CR111] 111.Han M, Smith SO, Sakmar TP. Constitutive activation of opsin by mutation of methionine 257 on transmembrane helix 6. Biochemistry. 1998;37:8253–8261. doi: 10.1021/bi980147r. [DOI] [PubMed] [Google Scholar]

[CR112] 112.Cai K, Klein-Seetharaman J, Hwa J, Hubbell WL, Khorana HG. Structure and function in rhodopsin: effects of disulfide cross-links in the cytoplasmic face of rhodopsin on transducin activation and phosphorylation by rhodopsin kinase. Biochemistry. 1999;38:12893–12898. doi: 10.1021/bi9912443. [DOI] [PubMed] [Google Scholar]

[CR113] 113.Ghanouni P, Gryczynski Z, Steenhuis JJ, et al. Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J Biol Chem. 2001;276:24433–24436. doi: 10.1074/jbc.C100162200. [DOI] [PubMed] [Google Scholar]

[CR114] 114.Janz JM, Farrens DL. Rhodopsin activation exposes a key hydrophobic binding site for the transducin alpha-subunit C terminus. J Biol Chem. 2004;279:29767–29773. doi: 10.1074/jbc.M402567200. [DOI] [PubMed] [Google Scholar]

[CR115] 115.Hubbell WL, Altenbach C, Hubbell CM, Khorana HG. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide crosslinking. Adv Protein Chem. 2003;63:243–290. doi: 10.1016/S0065-3233(03)63010-X. [DOI] [PubMed] [Google Scholar]

[CR116] 116.Lin SW, Sakmar TP. Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state. Biochemistry. 1996;35:11149–11159. doi: 10.1021/bi960858u. [DOI] [PubMed] [Google Scholar]

[CR117] 117.Altenbach C, Cai K, Khorana HG, Hubbell WL. Structural features and light-dependent changes in the sequence 306–322 extending from helix VII to the palmitoylation sites in rhodopsin: a sitedrected spin-labeling study. Biochemistry. 1999;38:7931–7937. doi: 10.1021/bi9900121. [DOI] [PubMed] [Google Scholar]

[CR118] 118.Altenbach C, Klein-Seetharaman J, Hwa J, Khorana HG, Hubbell WL. Structural features and light-dependent changes in the sequence 59–75 connecting helices I and II in rhodopsin: a site-directed spinlabeling study. Biochemistry. 1999;38:7945–7949. doi: 10.1021/bi990014l. [DOI] [PubMed] [Google Scholar]

[CR119] 119.Altenbach C, Cai K, Klein-Seetharaman J, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 65 in helix TM1 and residues in the sequence 306–319 at the cytoplasmic end of helix TM7 and in helix H8. Biochemistry. 2001;40:15483–15492. doi: 10.1021/bi011546g. [DOI] [PubMed] [Google Scholar]

[CR120] 120.Altenbach C, Klein-Seetharaman J, Cai K, Khorana HG, Hubbell WL. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 316 in helix 8 and residues in the sequence 60–75, covering the cytoplasmic end of helices TM1 and TM2 and their connection loop CL1. Biochemistry. 2001;40:15493–15500. doi: 10.1021/bi011545o. [DOI] [PubMed] [Google Scholar]

[CR121] 121.Gether U, Kobilka BK. G protein-coupled receptors. II. Mechanism of agonist activation. J Biol Chem. 1998;273:17979–17982. doi: 10.1074/jbc.273.29.17979. [DOI] [PubMed] [Google Scholar]

[CR122] 122.Devanathan S, Yao Z, Salamon Z, Kobilka B, Tollin G. Plasmon-waveguide resonance studies of ligand binding to the human beta 2-adrenergic receptor. Biochemistry. 2004;43:3280–3288. doi: 10.1021/bi035825a. [DOI] [PubMed] [Google Scholar]

[CR123] 123.Salamon Z, Cowell S, Varga E, Yamamura HI, Hruby VJ, Tollin G. Plasmon resonance studies of agonist/antagonist binding to the human delta-opioid receptor: new structural insights into receptor-ligand interactions. Biophys J. 2000;79:2463–2474. doi: 10.1016/S0006-3495(00)76489-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR124] 124.Salamon Z, Hruby VJ, Tollin G, Cowell S. Binding of agonists, antagonists and inverse agonists to the human delta-opioid receptor produces distinctly different conformational states distinguishable by plasmon-waveguide resonance spectroscopy. J Pept Res. 2002;60:322–328. doi: 10.1034/j.1399-3011.2002.21060.x. [DOI] [PubMed] [Google Scholar]

[CR125] 125.Alves ID, Ciano KA, Boguslavski V, et al. Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. J Biol Chem. 2004;279:44673–44682. doi: 10.1074/jbc.M404713200. [DOI] [PubMed] [Google Scholar]

[CR126] 126.Alves ID, Cowell SM, Salamon Z, Devanathan S, Tollin G, Hruby VJ. Different structural states of the proteolipid membrane are produced by ligand binding to the human delta-opioid receptor as shown by plasmon-waveguide resonance spectroscopy. Mol Pharmacol. 2004;65:1248–1257. doi: 10.1124/mol.65.5.1248. [DOI] [PubMed] [Google Scholar]

[CR127] 127.Tramontano A, Morea V. Exploiting evolutionary relationships for predicting protein structures. Biotechnol Bioeng. 2003;84:756–763. doi: 10.1002/bit.10850. [DOI] [PubMed] [Google Scholar]

[CR128] 128.Bates PA, Kelley LA, MacCallum RM, Sternberg MJ. Enhancement of protein modeling by human intervention in applying the automatic programs 3D-JIGSAW and 3D-PSSM.Proteins. 2001;39–46. [DOI] [PubMed]

[CR129] 129.Li X, Jacobson MP, Friesner RA. High-resolution prediction of protein helix positions and orientations. Proteins. 2004;55:368–382. doi: 10.1002/prot.20014. [DOI] [PubMed] [Google Scholar]

[CR130] 130.Evers A, Gohlke H, Klebe G. Ligand-supported homology modelling of protein binding-sites using knowledge-based potentials. J Mol Biol. 2003;334:327–345. doi: 10.1016/j.jmb.2003.09.032. [DOI] [PubMed] [Google Scholar]

[CR131] 131.Ward SD, Hamdan FF, Bloodworth LM, Wess J. Conformational changes that occur during M3 muscarinic acetylcholine receptor activation probed by the use of an in situ disulfide cross-linking strategy. J Biol Chem. 2002;277:2247–2257. doi: 10.1074/jbc.M107647200. [DOI] [PubMed] [Google Scholar]

[CR132] 132.Swaminath G, Lee TW, Kobilka B. Identification of an allosteric binding site for Zn2+ on the beta2 adrenergic receptor. J Biol Chem. 2003;278:352–356. doi: 10.1074/jbc.M206424200. [DOI] [PubMed] [Google Scholar]

[CR133] 133.Elling CE, Thirstrup K, Holst B, Schwartz TW. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor. Proc Natl Acad Sci USA. 1999;96:12322–12327. doi: 10.1073/pnas.96.22.12322. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR134] 134.Holst B, Elling CE, Schwartz TW. Partial agonism through a zincion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor. Mol Pharmacol. 2000;58:263–270. doi: 10.1124/mol.58.2.263. [DOI] [PubMed] [Google Scholar]

[CR135] 135.Lagerstrom MC, Klovins J, Fredriksson R, et al. High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3. J Biol Chem. 2003;278:51521–51526. doi: 10.1074/jbc.M307683200. [DOI] [PubMed] [Google Scholar]

[CR136] 136.Ewing TJ, Makino S, Skillman AG, Kuntz ID. DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des. 2001;15:411–428. doi: 10.1023/A:1011115820450. [DOI] [PubMed] [Google Scholar]

[CR137] 137.Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997;267:727–748. doi: 10.1006/jmbi.1996.0897. [DOI] [PubMed] [Google Scholar]

[CR138] 138.Rarey M, Wefing S, Lengauer T. Placement of medium-sized molecular fragments into active sites of proteins. J Comput Aided Mol Des. 1996;10:41–54. doi: 10.1007/BF00124464. [DOI] [PubMed] [Google Scholar]

[CR139] 139.Taylor RD, Jewsbury PJ, Essex JW. FDS: flexible ligand and receptor docking with a continuum solvent model and soft-core energy function. J Comput Chem. 2003;24:1637–1656. doi: 10.1002/jcc.10295. [DOI] [PubMed] [Google Scholar]

[CR140] 140.Halgren TA, Murphy RB, Friesner RA, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47:1750–1759. doi: 10.1021/jm030644s. [DOI] [PubMed] [Google Scholar]

[CR141] 141.Venkatachalam CM, Jiang X, Oldfield T, Waldman M. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graph Model. 2003;21:289–307. doi: 10.1016/S1093-3263(02)00164-X. [DOI] [PubMed] [Google Scholar]

[CR142] 142.Cavasotto CN, Abagan RA. Protein flexibility in ligand docking and virtual screening to protein kinases. J Mol Biol. 2004;337:209–225. doi: 10.1016/j.jmb.2004.01.003. [DOI] [PubMed] [Google Scholar]

[CR143] 143.Perola E, Walters WP, Charifson PS. A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins. 2004;56:235–249. doi: 10.1002/prot.20088. [DOI] [PubMed] [Google Scholar]

[CR144] 144.Halperin I, Ma B, Wolfson H, Nussinov R. Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins. 2004;47:409–443. doi: 10.1002/prot.10115. [DOI] [PubMed] [Google Scholar]

[CR145] 145.Kontoyianni M, McClellan LM, Sokol GS. Evaluation of docking performance: comparative data on docking algorithms. J Med Chem. 2004;47:558–565. doi: 10.1021/jm0302997. [DOI] [PubMed] [Google Scholar]

[CR146] 146.Carlson HA, McCammon JA. Accommodating protein flexibility in computational drug design. Mol Pharmacol. 2000;57:213–218. [PubMed] [Google Scholar]

[CR147] 147.Evers A, Klebe G. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Chem. 2004;47:5381–5392. doi: 10.1021/jm0311487. [DOI] [PubMed] [Google Scholar]

[CR148] 148.Heyl DL, Mosberg HI. Modification of the Phe3 aromatic moiety in delta receptor-selective dermorphin/deltorphin-related tetrapeptides: effects on opioid receptor binding. Int J Pept Protein Res. 1992;39:450–457. doi: 10.1111/j.1399-3011.1992.tb01449.x. [DOI] [PubMed] [Google Scholar]

[CR149] 149.Sebastian A, Bidlack JM, Jiang Q, et al. 14 beta-[(p-nitrocinnamoy 1)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity. J Med Chem. 1993;36:3154–3160. doi: 10.1021/jm00073a015. [DOI] [PubMed] [Google Scholar]

[CR150] 150.Sagara T, Egashira H, Okamura M, Fujii I, Shimohigashi Y, Kanematsu K. Ligand recognition in mu opioid receptor: experimentally based modeling of mu opioid receptor binding sites and their testing by ligand docking. Bioorg Med Chem. 1996;4:2151–2166. doi: 10.1016/S0968-0896(96)00219-2. [DOI] [PubMed] [Google Scholar]

[CR151] 151.Chabre M, Breton J. Orientation of aromatic residues in rhodopsin: rotation of one tryptophan upon the meta I to meta II transition after illumination. Photochem Photobiol. 1979;30:295–299. doi: 10.1111/j.1751-1097.1979.tb07150.x. [DOI] [PubMed] [Google Scholar]

[CR152] 152.Baneres JL, Martin A, Hullot P, Girard JP, Rossi JC, Parello J. Structure-based analysis of GPCR function: conformational adaptation of both agonist and receptor upon leukotriene B4 binding to recombinant BLT1. J Mol Biol. 2003;329:801–814. doi: 10.1016/S0022-2836(03)00438-8. [DOI] [PubMed] [Google Scholar]

[CR153] 153.Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GF. Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004;23:3609–3620. doi: 10.1038/sj.emboj.7600374. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR154] 154.Sammes PG, Taylor JB. Opioid receptors. In: Hansch C, editor. Comprehensive Medicinal Chemistry. Oxford, UK: Pergamon Press; 1990. pp. 805–844. [Google Scholar]

[CR155] 155.Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Lu Y. Conversion of μ-, δ- and κ-receptor selective opioid peptide agonists into μ-, δ-, and κ-receptor selective antagonists. Life Sci. 2003;73:691–698. doi: 10.1016/S0024-3205(03)00389-8. [DOI] [PubMed] [Google Scholar]

[CR156] 156.Huang P, Kim S, Loew G. Development of a common 3D pharmacophore for delta-opioid recognition from peptides and non-peptides using a novel computer program. J Comput Aided Mol Des. 1997;11:21–28. doi: 10.1023/A:1008067209563. [DOI] [PubMed] [Google Scholar]

[CR157] 157.Filizola M, Villar HO, Loew GH. Molecular determinants of non-specific recognition of delta, mu, and kappa opioid receptors. Bioorg Med Chem. 2001;9:69–76. doi: 10.1016/S0968-0896(00)00223-6. [DOI] [PubMed] [Google Scholar]

[CR158] 158.Filizola M, Villar HO, Loew GH. Differentiation of delta, mu, and kappa opioid receptor agonists based on pharmacophore development and computed physicochemical properties. J Comput Aided Mol Des. 2001;15:297–307. doi: 10.1023/A:1011187320095. [DOI] [PubMed] [Google Scholar]

[CR159] 159.Bernard D, Coop A, MacKerell AD. 2D conformationally sampled pharmacophore: a ligand-based pharmacophore to differentiate delta opioid agonists from antagonists. J Am Chem Soc. 2003;125:3101–3107. doi: 10.1021/ja027644m. [DOI] [PubMed] [Google Scholar]

PERMALINK

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Irina D Pogozheva

Magdalena J Przydzial

Henry I Mosberg

Abstract

Full Text

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Homology modeling of opioid receptor-ligand complexes using experimental constraints

Irina D Pogozheva

Magdalena J Przydzial

Henry I Mosberg

Abstract

Full Text

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases