Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

Nature Chemical Biology

Volumn 14, Issue 2, 2018, Pages 126-134

  McCorvy, John D ^a   Butler, Kyle V ^b   Kelly, Brendan ^c   Rechsteiner, Katie ^a   Karpiak, Joel ^d   Betz, Robin M ^c   Kormos, Bethany L ^e   Shoichet, Brian K ^d   Dror, Ron O ^c   Jin, Jian ^a   Roth, Bryan L ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c STANFORD UNIVERSITY   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; ARIPIPRAZOLE; BETA ARRESTIN; G PROTEIN COUPLED RECEPTOR; INDOLE DERIVATIVE; LIGAND; ARRB1 PROTEIN, HUMAN; BETA ARRESTIN 1; CYCLIC AMP; PROTEIN BINDING; SERINE;

AGONIST; ARTICLE; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG STRUCTURE; MOLECULAR INTERACTION; PRIORITY JOURNAL; PROTEIN INTERACTION; SIGNAL TRANSDUCTION; CHEMISTRY; DRUG DEVELOPMENT; HEK293 CELL LINE; HUMAN; HYDROGEN BOND; KINETICS; MOLECULAR DYNAMICS; MUTATION; PROTEIN CONFORMATION; X RAY CRYSTALLOGRAPHY;

ARIPIPRAZOLE; BETA-ARRESTIN 1; CRYSTALLOGRAPHY, X-RAY; CYCLIC AMP; DRUG DESIGN; DRUG DISCOVERY; HEK293 CELLS; HUMANS; HYDROGEN BONDING; INDOLES; KINETICS; LIGANDS; MOLECULAR DYNAMICS SIMULATION; MUTATION; PROTEIN BINDING; PROTEIN CONFORMATION; RECEPTORS, G-PROTEIN-COUPLED; SERINE; SIGNAL TRANSDUCTION;

EID: 85040926100     PISSN: 15524450     EISSN: 15524469     Source Type: Journal    
DOI: 10.1038/nchembio.2527     Document Type: Article

References (59)

1. Overington, J.P., Al-Lazikani, B, &Hopkins, A.L, How many drug targets are there? Nat, Rev, Drug Discov, 5, 993-996 (2006).
2. Rask-Andersen, M., Almén, M.S, &Schiöth, H.B, Trends in the exploitation of novel drug targets, Nat, Rev, Drug Discov, 10, 579-590 (2011).
3. Wacker, D., Stevens, R.C, &Roth, B.L, How ligands illuminate GPCR molecular pharmacology, Cell 170, 414-427 (2017).
4. Urban, J.D, et al, Functional selectivity and classical concepts of quantitative pharmacology, J, Pharmacol, Exp, Ther, 320, 1-13 (2007).
5. DeWire, S.M., Ahn, S., Lefkowitz, R.J, &Shenoy, S.K, β-arrestins and cell signaling, Annu, Rev, Physiol, 69, 483-510 (2007).
6. Shukla, A.K., Xiao, K, &Lefkowitz, R.J, Emerging paradigms of β-arrestindependent seven transmembrane receptor signaling, Trends Biochem, Sci, 36, 457-469 (2011).
7. Violin, J.D., Crombie, A.L., Soergel, D.G, &Lark, M.W, Biased ligands at G-protein-coupled receptors: promise and progress, Trends Pharmacol, Sci, 35, 308-316 (2014).
8. Allen, J.A, et al, Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy, Proc, Natl, Acad, Sci, USA 108, 18488-18493 (2011).
9. Soergel, D.G, et al, Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers, Pain 155, 1829-1835 (2014).
10. Violin, J.D, et al, Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance, J, Pharmacol, Exp, Ther, 335, 572-579 (2010).
11. Urs, N.M, et al, Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease, Proc, Natl, Acad, Sci, USA 112, E2517-E2526 (2015).
12. Charfi, I., Audet, N., Bagheri Tudashki, H, &Pineyro, G, Identifying ligand-specific signalling within biased responses: focus on δ opioid receptor ligands, Br, J, Pharmacol, 172, 435-448 (2015).
13. Manglik, A, et al, Structure-based discovery of opioid analgesics with reduced side effects, Nature 537, 185-190 (2016).
14. DeWire, S.M, et al, A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine, J, Pharmacol, Exp, Ther, 344, 708-717 (2013).
15. Gesty-Palmer, D, et al, β-arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo, Mol, Endocrinol, 27, 296-314 (2013).
16. Masri, B, et al, Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics, Proc, Natl, Acad, Sci, USA 105, 13656-13661 (2008).
17. Tchernychev, B, et al, Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells, Proc, Natl, Acad, Sci, USA 107, 22255-22259 (2010).
18. Cherezov, V, et al, High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor, Science 318, 1258-1265 (2007).
19. Chien, E.Y, et al, Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist, Science 330, 1091-1095 (2010).
20. Rasmussen, S.G, et al, Crystal structure of the β2 adrenergic receptor-Gs protein complex, Nature 477, 549-555 (2011).
21. Ring, A.M, et al, Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody, Nature 502, 575-579 (2013).
22. Wacker, D, et al, Structural features for functional selectivity at serotonin receptors, Science 340, 615-619 (2013).
23. Wang, C, et al, Structural basis for molecular recognition at serotonin receptors, Science 340, 610-614 (2013).
24. Kapur, S, &Remington, G, Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia, Annu, Rev, Med, 52, 503-517 (2001).
25. Wadenberg, M.L., Soliman, A., VanderSpek, S.C, &Kapur, S, Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects, Neuropsychopharmacology 25, 633-641 (2001).
26. Shapiro, D.A, et al, Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology, Neuropsychopharmacology 28, 1400-1411 (2003).
27. Chen, X, et al, Discovery of G protein-biased D2 dopamine receptor partial agonists, J, Med, Chem, 59, 10601-10618 (2016).
28. Park, S.M, et al, Effects of β-arrestin-biased dopamine D2 receptor ligands on schizophrenia-like behavior in hypoglutamatergic mice .Neuropsychopharmacology 41, 704-715 (2016).
29. Ambrosio, C., Molinari, P., Cotecchia, S, &Costa, T, Catechol-binding serines of β2-adrenergic receptors control the equilibrium between active and inactive receptor states, Mol, Pharmacol, 57, 198-210 (2000).
30. Isogai, S, et al, Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor, Nature 530, 237-241 (2016).
31. Warne, T, et al, The structural basis for agonist and partial agonist action on a β1-adrenergic receptor, Nature 469, 241-244 (2011).
32. Neve, K.A, &Wiens, B.L, Four ways of being an agonist: multiple sequence determinants of efficacy at D2 dopamine receptors, Biochem, Soc, Trans, 23, 112-116 (1995).
33. Wiens, B.L., Nelson, C.S, &Neve, K.A, Contribution of serine residues to constitutive and agonist-induced signaling via the D2S dopamine receptor: evidence for multiple, agonist-specific active conformations, Mol, Pharmacol, 54, 435-444 (1998).
34. Fowler, J.C., Bhattacharya, S., Urban, J.D., Vaidehi, N, &Mailman, R.B, Receptor conformations involved in dopamine D(2L) receptor functional selectivity induced by selected transmembrane-5 serine mutations, Mol, Pharmacol, 81, 820-831 (2012).
35. Wacker, D, et al, Crystal structure of an LSD-bound human serotonin receptor, Cell 168, 377-389.e12 (2017).
36. Chen, X, et al, Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D2 receptor agonists, J, Med, Chem, 55, 7141-7153 (2012).
37. Christopher, J.A, et al, Biophysical fragment screening of the β1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design, J, Med, Chem, 56, 3446-3455 (2013).
38. Kling, R.C., Tschammer, N., Lanig, H., Clark, T, &Gmeiner, P, Active-state model of a dopamine D2 receptor-Gai complex stabilized by aripiprazoletype partial agonists, PLoS One 9, e100069 (2014).
39. Luedtke, R.R, et al, Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds, ACS Chem, Neurosci, 3, 1050-1062 (2012).
40. Kroeze, W.K, et al, PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome, Nat, Struct, Mol, Biol, 22, 362-369 (2015).
41. Klein Herenbrink, C, et al, The role of kinetic context in apparent biased agonism at GPCRs, Nat, Commun, 7, 10842 (2016).
42. Ahuja, S, et al, Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation, Nat, Struct, Mol, Biol, 16, 168-175 (2009).
43. Kuwayama, S., Imai, H., Hirano, T., Terakita, A, &Shichida, Y, Conserved proline residue at position 189 in cone visual pigments as a determinant of molecular properties different from rhodopsins, Biochemistry 41, 15245-15252 (2002).
44. Warne, T, &Tate, C.G, The importance of interactions with helix 5 in determining the efficacy of β-adrenoceptor ligands, Biochem, Soc, Trans, 41, 159-165 (2013).
45. Deupi, X, &Standfuss, J, Structural insights into agonist-induced activation of G-protein-coupled receptors, Curr, Opin, Struct, Biol, 21, 541-551 (2011).
46. Roth, B.L., Sheffler, D.J, &Kroeze, W.K, Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia, Nat, Rev, Drug Discov, 3, 353-359 (2004).
47. Besnard, J, et al, Automated design of ligands to polypharmacological profiles, Nature 492, 215-220 (2012).
48. Huang, W, et al, Structural insights into μ-opioid receptor activation, Nature 524, 315-321 (2015).
49. Kobilka, B, &Schertler, G.F, New G-protein-coupled receptor crystal structures: insights and limitations, Trends Pharmacol, Sci, 29, 79-83 (2008).
50. Weiss, D.R, et al, Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor, ACS Chem, Biol, 8, 1018-1026 (2013).
51. Coleman, R.G., Sterling, T, &Weiss, D.R, SAMPL4 &DOCK3.7: lessons for automated docking procedures, J, Comput, Aided Mol, Des, 28, 201-209 (2014).
52. Lomize, M.A., Lomize, A.L., Pogozheva, I.D, &Mosberg, H.I, OPM: orientations of proteins in membranes database, Bioinformatics 22, 623-625 (2006).
53. Zhang, L, &Hermans, J, Hydrophilicity of cavities in proteins, Proteins 24, 433-438 (1996).
54. Best, R.B, et al, Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone and side-chain (1) and (2) dihedral angles, J, Chem, Theory Comput, 8, 3257-3273 (2012).
55. Vanommeslaeghe, K, &MacKerell, A.D, Jr, Automation of the CHARMM general force field (CGenFF) I: bond perception and atom typing, J, Chem, Inf, Model, 52, 3144-3154 (2012).
56. Betz, R.M, &Walker, R.C, Paramfit: automated optimization of force field parameters for molecular dynamics simulations, J, Comput, Chem, 36, 79-87 (2015).
57. Salomon-Ferrer, R., Götz, A.W., Poole, D., Le Grand, S, &Walker, R.C, Routine microsecond molecular dynamics simulations with AMBER on GPUs, Explicit solvent particle mesh ewald, J, Chem, Theory Comput, 9, 3878-3888 (2013).
58. Humphrey, W., Dalke, A, &Schulten, K, VMD: visual molecular dynamics, J, Mol, Graph, 14, 33-38 (1996).
59. Roe, D.R, &Cheatham, T.E, III, PTRAJ and CPPTRAJ: software for processing and analysis of molecular synamics trajectory data, J, Chem, Theory Comput, 9, 3084-3095 (2013).