Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

AAPS Journal

Volumn 17, Issue 5, 2015, Pages 1080-1095

  Feng, Zhiwei ^a,b,c   Hu, Guanxing ^a,b,c   Ma, Shifan ^a,b,c   Xie, Xiang Qun ^a,b,c,d  

^a Universigy of Pittsburgh   (United States)

^b NIDA National Center of Excellence for Computational Drug Abuse Research   (United States)

^c Drug Discovery Institute   (United States)

^d UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

allosteric modulators; bitopic ligands; computational approaches; drug discovery; drug target discovery; G protein coupled receptors

Indexed keywords

ADX 10059; ADX 48621; CINACALCET; CYM 5541; DISULFIDE; DRUG; FENOBAM; G PROTEIN COUPLED RECEPTOR; MARAVIROC; MAVOGLURANT; MDAN 21; MUSCARINIC M2 RECEPTOR AGONIST; MUSCARINIC M2 RECEPTOR AGONIST 1; MUSCARINIC M2 RECEPTOR AGONIST 2; REPARIXIN; SB2 69652; SPM 242; SUMATRIPTAN; THRX 160209; UNCLASSIFIED DRUG; VCP 171; [4 [(3 CHLOROPHENYL)CARBAMOYLOXY] 2 BUTYNYL]TRIMETHYLAMMONIUM; LIGAND;

ALLOSTERISM; ANALYTIC METHOD; ARTICLE; BINDING AFFINITY; BINDING SITE; COMPUTATIONAL FRAGMENT BASED DRUG DESIGN; CONFORMATIONAL DYNAMICS BASED APPROACH; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SENSITIZATION; DRUG STRUCTURE; DRUG TARGETING; HIGH THROUGHPUT SCREENING; HUMAN; MOLECULAR DOCKING; MOLECULAR DYNAMICS; MOLECULAR SYSTEMATICS; NORMAL MODEL ANALYSIS BASED APPROACH; PHARMACOPHORE; SEQUENCE BASED APPROACH; STRUCTURE BASED METHOD; STRUCTURE BASED VIRTUAL SCREENING; SUPPORT VECTOR MACHINE; COMPUTER AIDED DESIGN; COMPUTER SIMULATION; DRUG DESIGN; DRUG DEVELOPMENT; METABOLISM; PROCEDURES;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; COMPUTER SIMULATION; COMPUTER-AIDED DESIGN; DRUG DESIGN; DRUG DISCOVERY; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; LIGANDS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84939564119     PISSN: None     EISSN: 15507416     Source Type: Journal    
DOI: 10.1208/s12248-015-9776-y     Document Type: Article

References (100)

1. Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev. 2010;62:265–304.
2. Feng Z, Hou T, Li Y. Studies on the interactions between β2 adrenergic receptor and Gs protein by molecular dynamics simulations. J Chem Inf Model. 2012;52:1005–14.
3. Feng Z, Hou T, Li Y. Selectivity and activation of dopamine D3R from molecular dynamics. J Mol Model. 2012;18:5051–63.
4. Feng Z, Hou T, Li Y. Docking and MD study of histamine H4R based on the crystal structure of H1R. J Mol Graph Model. 2013;39:1–12.
5. Feng Z, Alqarni MH, Yang P, Tong Q, Chowdhury A, Wang L, et al. Modeling, molecular dynamics simulation and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model. 2014;54:2483–99.
6. Bridges TM, Lindsley CW. G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol. 2008;3:530–41.
7. Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW. Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol. 2014;54:165–84.
8. Wellendorph P, Bräuner‐Osborne H. Molecular basis for amino acid sensing by family CG‐protein‐coupled receptors. Brit J Pharmacol. 2009;156:869–84.
9. Flor PJ, Acher FC. Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem Pharmacol. 2012;84:414–24.
10. Fenton AW. Allostery: an illustrated definition for the ‘second secret of life’. Trends Biochem Sci. 2008;33:420–5.
11. Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8:41–54.
12. Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev. 2002;54:323–74.
13. Lane JR, Abdul-Ridha A, Canals M. Regulation of G protein-coupled receptors by allosteric ligands. ACS Chem Neurosci. 2013;4:527–34.
14. Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, et al. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem. 2012;55:1445–64.
15. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, et al. ASD v2.0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res. 2014;42:D510–6.
16. Möhler H, Fritschy J, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2–8.
17. Epping-Jordan M, Le Poul E, Rocher J-P. Allosteric modulation: a novel approach to drug discovery. Innovations Pharm Technol. 2007;24:24–6.
18. Burford NT, Watson J, Bertekap R, Alt A. Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem Pharmacol. 2011;81:691–702.
19. Dalton J, Gómez-Santacana X, Llebaria A, Giraldo J. A computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (In) activation. J Chem Inf Model. 2014;54:1476–87.
20. Kamal M, Jockers R. Bitopic ligands: all-in-one orthosteric and allosteric. F1000 Biol Rep. 2009;1:77.
21. Davie BJ, Christopoulos A, Scammells PJ. Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. ACS Chem Neurosci. 2013;4:1026–48.
22. Valant C, Sexton PM, Christopoulos A. Orthosteric/allosteric bitopic ligands. Mol Interv. 2009;9:125.
23. Valant C, Robert Lane J, Sexton PM, Christopoulos A. The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol. 2012;52:153–78.
24. Jo E, Bhhatarai B, Repetto E, Guerrero M, Riley S, Brown SJ, et al. Novel selective allosteric and bitopic ligands for the S1P3 receptor. ACS Chem Biol. 2012;7:1975–83.
25. Lane JR, Sexton PM, Christopoulos A. Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci. 2013;34:59–66.
26. Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, et al. A new mechanism of allostery in a G protein–coupled receptor dimer. Nat Chem Biol. 2014;10:745–52.
27. Maggio R., Scarselli M., Capannolo M., Millan M. J. Novel dimensions of D3 receptor function: focus on heterodimerisation, transactivation and allosteric modulation. Eur Neuropsychopharm. 2014.
28. Ahn KH, Mahmoud MM, Kendall DA. Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. J Biol Chem. 2012;287:12070–82.
29. Lane JR, Chubukov P, Liu W, Canals M, Cherezov V, Abagyan R, et al. Structure-based ligand discovery targeting orthosteric and allosteric pockets of dopamine receptors. Mol Pharmacol. 2013;84:794–807.
30. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 2013;504:101–6.
31. Shore DM, Baillie GL, Hurst DH, Navas F, Seltzman HH, Marcu JP, et al. Allosteric modulation of a cannabinoid G protein-coupled receptor binding site elucation and relationship to G protein signaling. J Biol Chem. 2014;289:5828–45.
32. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51.
33. Feldman T, Kabaleeswaran V, Jang SB, Antczak C, Djaballah H, Wu H, et al. A class of allosteric caspase inhibitors identified by high-throughput screening. Mol Cell. 2012;47:585–95.
34. Jahnke W, Rondeau J-M, Cotesta S, Marzinzik A, Pellé X, Geiser M, et al. Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat Chem Biol. 2010;6:660–6.
35. Plosker GL. Cinacalcet Pharm Econ. 2011;29:807.
36. Maraviroc: Reactivation of hepatitis B virus infection in an elderly patient: case report. Reactions Weekly 2014; 1508: 24–24.
37. Zarbock A, Allegretti M, Ley K. Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice. Brit J Pharmacol. 2008;155:357–64.
38. Addex presents ADX10059 GERD data at conference. Chem Bus Newsbase. 2007: 1.
39. Addex announces ADX10059 phase IIa acute anxiety data. Chem Bus Newsbase. 2008: 1.
40. Berg D, Godau J, Trenkwalder C, Eggert K, Csoti I, Storch A, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011;26:1243–50.
41. Girard F, Keywood C, Poli SP, Mutel V. Anti-parkinsonian effects of ADX48621 a mGluR5 negative allosteric modulator, in the rat haloperidol induced catalepsy model. Mov Disord. 2010;25:S282.
42. Sourial M, Cheng C, Doering LC. Progress toward therapeutic potential for AFQ056 in fragile X syndrome. J Exp Pharmacol. 2013;2013:45–54.
43. In; Wiley Periodicals, Inc: 2009; Vol. 11, p 7.
44. Lavreysen H, Langlois X, Ahnaou A, Drinkenburg W, te Riele P, Biesmans I, et al. Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H] JNJ-40068782. J Pharmacol Exp Ther. 2013;346:514–27.
45. Hopkins CR. Is there a path forward for mGlu2 positive allosteric modulators for the treatment of schizophrenia? ACS Chem Neurosci. 2013;4:211–3.
46. Macdonald GJ, Lindsley CW. A unique industrial–academic collaboration towards the next generation of schizophrenia therapeutics. Curr Top Med Chem. 2014;14:304–12.
47. Lindsley CW, Hopkins CR. Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson’s disease: historical perspective and review of the patent literature. Expert Opin Ther Pat. 2012;22:461–81.
48. Taylor SG, Riley G, Hunter AJ, Stemp G, Routledge C, Hagan JJ, et al. SB-269652 is a selective D3 receptor antagonist in vitro and in vivo. Eur Neuropsychopharm. 1999;9:266.
49. Silvano E, Millan MJ, la Cour CM, Han Y, Duan L, Griffin SA, et al. The tetrahydroisoquinoline derivative SB269, 652 is an allosteric antagonist at dopamine D3 and D2 receptors. Mol Pharmacol. 2010;78:925–34.
50. Tahtaoui C, Parrot I, Klotz P, Guillier F, Galzi J-L, Hibert M, et al. Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor. J Med Chem. 2004;47:4300–15.
51. Valant C, Gregory KJ, Hall NE, Scammells PJ, Lew MJ, Sexton PM, et al. A novel mechanism of G protein-coupled receptor functional selectivity muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand. J Biol Chem. 2008;283:29312–21.
52. Lu S, Huang W, Zhang J. Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today. 2014;19:1595–600.
53. Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012;337:232–6.
54. Fenalti G, Giguere PM, Katritch V, Huang X-P, Thompson AA, Cherezov V, et al. Molecular control of δ-opioid receptor signalling. Nature. 2014;506:191–6.
55. Tesileanu T., Colwell L. J., Leibler S. Protein sectors: statistical coupling analysis versus conservation. Quant. Biol. 2014: 1–31.
56. Gasper PM, Fuglestad B, Komives EA, Markwick PR, McCammon JA. Allosteric networks in thrombin distinguish procoagulant vs. anticoagulant activities. Proc Natl Acad Sci U S A. 2012;109:21216–22.
57. Van Wart AT, Durrant J, Votapka L, Amaro RE. Weighted Implementation of Suboptimal Paths (WISP): an optimized algorithm and tool for dynamical network analysis. J Chem Theory Comput. 2014;10:511–7.
58. McLaughlin Jr RN, Poelwijk FJ, Raman A, Gosal WS, Ranganathan R. The spatial architecture of protein function and adaptation. Nature. 2012;491:138–42.
59. Reynolds KA, McLaughlin RN, Ranganathan R. Hotspots for allosteric regulation on protein surfaces. Cell. 2011;147:1564–75.
60. Le Guilloux V, Schmidtke P, Tuffery P. Fpocket: an open source platform for ligand pocket detection. BMC Bioinforma. 2009;10:168.
61. Huang W, Lu S, Huang Z, Liu X, Mou L, Luo Y, et al. Allosite: a method for predicting allosteric sites. Bioinformatics. 2013;29:2357–9.
62. Baskaran SK, Goswami N, Selvaraj S, Muthusamy VS, Lakshmi BS. Molecular dynamics approach to probe the allosteric inhibition of PTP1B by chlorogenic and cichoric acid. J Chem Inf Model. 2012;52:2004–12.
63. Dror RO, Green HF, Valant C, Borhani DW, Valcourt JR, Pan AC, et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature. 2013;503:295–9.
64. Matosin N, Fernandez-Enright F, Frank E, Deng C, Wong J, Huang X-F, et al. Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. J Psychiatr Neurosci. 2014;39:407.
65. Yuan Y, Pei J, Lai L. Binding site detection and druggability prediction of protein targets for structure-based drug design. Curr Pharm Des. 2013;19:2326–33.
66. Ivetac A, McCammon JA. Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach. Chem Biol Drug Des. 2010;76:201–17.
67. Ngan CH, Bohnuud T, Mottarella SE, Beglov D, Villar EA, Hall DR, et al. FTMAP: extended protein mapping with user-selected probe molecules. Nucleic Acids Res. 2012;40:W271–5.
68. Qi Y, Wang Q, Tang B, Lai L. Identifying allosteric binding sites in proteins with a two-state G̅o model for novel allosteric effector discovery. J Chem Theory Comput. 2012;8:2962–71.
69. Bahar I, Lezon TR, Bakan A, Shrivastava IH. Normal mode analysis of biomolecular structures: functional mechanisms of membrane proteins. Chem Rev. 2009;110:1463–97.
70. Panjkovich A, Daura X. PARS: a web server for the prediction of protein allosteric and regulatory sites. Bioinformatics. 2014;30:1314–5.
71. Goncearenco A, Mitternacht S, Yong T, Eisenhaber B, Eisenhaber F, Berezovsky IN. SPACER: server for predicting allosteric communication and effects of regulation. Nucleic Acids Res. 2013;41:W266–72.
72. Mitternacht S, Berezovsky IN. A geometry-based generic predictor for catalytic and allosteric sites. Protein Eng Des Sel. 2011;24:405–9.
73. Mitternacht S, Berezovsky IN. Binding leverage as a molecular basis for allosteric regulation. PLoS Comput Biol. 2011;7:l.e1002148.
74. Hocker HJ, Rambahal N, Gorfe AA. LIBSA—a method for the determination of ligand-binding preference to allosteric sites on receptor ensembles. J Chem Inf Model. 2014;54:530.
75. Castelli MP, Casu A, Casti P, Lobina C, Carai MA, Colombo G, et al. Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABAB receptor. J Pharmacol Exp Ther. 2012;340:529–38.
76. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, et al. Positive allosteric modulation of native and recombinant γ-aminobutyric acidB receptors by 2, 6-Di-tert-butyl-4-(3-hydroxy-2, 2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol Pharmacol. 2001;60:963–71.
77. B receptors. Bioorg Med Chem Lett. 2007;17:6206–11.
78. Malherbe P, Masciadri R, Norcross R, Knoflach F, Kratzeisen C, Zenner MT, et al. Characterization of (R, S)-5, 7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors. Brit J Pharmacol. 2008;154:797–811.
79. B receptor. Adv Pharmacol. 2010;58:1–18.
80. Kubas H, Meyer U, Krueger B, Hechenberger M, Vanejevs M, Zemribo R, et al. Discovery, synthesis, and structure–activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators. Bioorg Med Chem Lett. 2013;23:4493–500.
81. Renner S, Noeske T, Parsons CG, Schneider P, Weil T, Schneider G. New allosteric modulators of metabotropic glutamate receptor 5 (mGluR5) found by ligand‐based virtual screening. ChemBioChem. 2005;6:620–5.
82. Noeske T, Jirgensons A, Starchenkovs I, Renner S, Jaunzeme I, Trifanova D, et al. Virtual screening for selective allosteric mGluR1 antagonists and structure–activity relationship investigations for coumarine derivatives. ChemMedChem. 2007;2:1763–73.
83. Hamon V., Bourgeas R., Ducrot P., Theret I., Xuereb L., Basse M. J., Brunel J. M., Combes S., Morelli X., Roche P. 2P2IHUNTER: a tool for filtering orthosteric protein–protein interaction modulators via a dedicated support vector machine. J R Soc Interface. 2013; 11.
84. Wang CI, Lewis RJ. Emerging opportunities for allosteric modulation of G-protein coupled receptors. Biochem Pharmacol. 2013;85:153–62.
85. Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science. 2010;330:1091–5.
86. Katritch V, Rueda M, Abagyan R. Ligand-guided receptor optimization. Meth Mol Biol. 2012;857:189–205.
87. Abagyan RA, Orry A, Raush E, Budagyan L, Totrov M. ICM manual. La Jolla: MolSoft LLC; 2012.
88. Radestock S, Weil T, Renner S. Homology model-based virtual screening for GPCR ligands using docking and target-biased scoring. J Chem Inf Model. 2008;48:1104–17.
89. Feng Z., Ma S., Hu G., Xie X.-Q. Allosteric binding site and activation mechanism of class C G-protein coupled receptors: metabotropic glutamate receptor family. AAPS J. 2015: 1–17.
90. Schwyzer R. ACTH: a short introductory review*. Ann NY Acad Sci. 1977;297:3–26.
91. Portoghese PS. Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol Sci. 1989;10:230–5.
92. Halazy S. G-protein coupled receptors bivalent ligands and drug design. Expert Opin Ther Pat. 1999;9:431–46.
93. Christopoulos A, Mitchelson F. Pharmacological analysis of the mode of interaction of McN-A-343 at atrial muscarinic M2 receptors. Eur J Pharmacol. 1997;339:153–6.
94. Steinfeld T, Mammen M, Smith JAM, Wilson RD, Jasper JR. A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor. Mol Pharmacol. 2007;72:291–302.
95. Antony J, Kellershohn K, Mohr-Andrä M, Kebig A, Prilla S, Muth M, et al. Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB J. 2009;23:442–50.
96. Mammen M, Choi S-K, Whitesides GM. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Edit. 1998;37:2754–94.
97. Maksay G. Allostery in pharmacology: thermodynamics, evolution and design. Prog Biophys Mol Biol. 2011;106:463–73.
98. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23:3–25.
99. Oguievetskaia K, Martin-Chanas L, Vorotyntsev A, Doppelt-Azeroual O, Brotel X, Adcock SA, et al. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site. J Comput-Aid Mol Des. 2009;23:571–82.
100. Lewis JA, Lebois EP, Lindsley CW. Allosteric modulation of kinases and GPCRs: design principles and structural diversity. Curr Opin Chem Biol. 2008;12:269–80.