Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

Proceedings of the National Academy of Sciences of the United States of America

Volumn 113, Issue 38, 2016, Pages E5675-E5684

  Miao, Yinglong ^a,b   Goldfeld, Dahlia Anne ^b   Moo, Ee Von ^c   Sexton, Patrick M ^c   Christopoulos, Arthur ^c   McCammon, J Andrew ^a,b   Valant, Celine ^c  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c MONASH UNIVERSITY   (Australia)

Author keywords

Affinity; Allosteric modulators; Cooperativity; Ensemble docking; GPCR

Indexed keywords

G PROTEIN COUPLED RECEPTOR; METHYLSCOPOLAMINE; MUSCARINIC AGENT; MUSCARINIC M1 RECEPTOR; MUSCARINIC M2 RECEPTOR; MUSCARINIC M3 RECEPTOR; MUSCARINIC RECEPTOR BLOCKING AGENT; NSC 121868; NSC 13316; NSC 147866; NSC 322661; NSC 99657; UNCLASSIFIED DRUG; LEAD; LIGAND;

ALLOSTERISM; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DISSOCIATION; DRUG DESIGN; DRUG SELECTIVITY; MOLECULAR DOCKING; MOLECULAR DYNAMICS; PRIORITY JOURNAL; SIMULATION; STRUCTURE ACTIVITY RELATION; VESTIBULE; WORKFLOW; AGONISTS; ALLOSTERIC SITE; ANIMAL; ANTAGONISTS AND INHIBITORS; BINDING COMPETITION; CHEMISTRY; CHO CELL LINE; CRICETULUS; DRUG EFFECTS; HUMAN; KINETICS; PROTEIN CONFORMATION; RADIOASSAY;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; ANIMALS; BINDING, COMPETITIVE; CHO CELLS; CRICETULUS; HUMANS; KINETICS; LEAD; LIGANDS; MOLECULAR DOCKING SIMULATION; MOLECULAR DYNAMICS SIMULATION; PROTEIN CONFORMATION; RADIOLIGAND ASSAY; RECEPTOR, MUSCARINIC M1; RECEPTOR, MUSCARINIC M2; RECEPTOR, MUSCARINIC M3; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84988672537     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1612353113     Document Type: Article

References (50)

1. Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993-996.
2. Neubig RR, Spedding M, Kenakin T, Christopoulos A; International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (2003) International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology. Pharmacol Rev 55(4):597-606.
3. Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nat Rev Drug Discov 1(3):198-210.
4. Shoichet BK, Kobilka BK (2012) Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol Sci 33(5):268-272.
5. Weiss DR, et al. (2013) Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor. ACS Chem Biol 8(5):1018-1026.
6. Kruse AC, et al. (2013) Muscarinic receptors as model targets and antitargets for structure-based ligand discovery. Mol Pharmacol 84(4):528-540.
7. Booth B, Zemmel R (2004) Prospects for productivity. Nat Rev Drug Discov 3(5):451-456.
8. Allen JA, Roth BL (2011) Strategies to discover unexpected targets for drugs active at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 51:117-144.
9. Caulfield MP, Birdsall NJ (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50(2):279-290.
10. Ivetac A, McCammon JA (2012) A molecular dynamics ensemble-based approach for the mapping of druggable binding sites. Methods Mol Biol 819:3-12.
11. Miao Y, Nichols SE, McCammon JA (2014) Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor. Chem Biol Drug Des 83(2):237-246.
12. Christopoulos A (2014) Advances in G protein-coupled receptor allostery: From function to structure. Mol Pharmacol 86(5):463-478.
13. Christopoulos A, Kenakin T (2002) G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54(2):323-374.
14. Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: Implications for drug discovery. Nat Rev Drug Discov 12(8):630-644.
15. Conn PJ, Christopoulos A, Lindsley CW (2009) Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8(1):41-54.
16. Haga K, et al. (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482(7386):547-551.
17. Kruse AC, et al. (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482(7386):552-556.
18. Kruse AC, et al. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504(7478):101-106.
19. Thal DM, et al. (2016) Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531(7594):335-340.
20. Dror RO, et al. (2011) Activation mechanism of the β2-adrenergic receptor. Proc Natl Acad Sci USA 108(46):18684-18689.
21. Niesen MJM, Bhattacharya S, Vaidehi N (2011) The role of conformational ensembles in ligand recognition in G-protein coupled receptors. J Am Chem Soc 133(33):13197-13204.
22. Provasi D, Artacho MC, Negri A, Mobarec JC, Filizola M (2011) Ligand-induced modulation of the free-energy landscape of G protein-coupled receptors explored by adaptive biasing techniques. PLOS Comput Biol 7(10):e1002193.
23. Kohlhoff KJ, et al. (2014) Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways. Nat Chem 6(1):15-21.
24. Shan J, Khelashvili G, Mondal S, Mehler EL, Weinstein H (2012) Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties. PLOS Comput Biol 8(4):e1002473.
25. Grossfield A (2011) Recent progress in the study of G protein-coupled receptors with molecular dynamics computer simulations. Biochim Biophys Acta 1808(7):1868-1878.
26. Johnston JM, Filizola M (2011) Showcasing modern molecular dynamics simulations of membrane proteins through G protein-coupled receptors. Curr Opin Struct Biol 21(4):552-558.
27. Vanni S, Rothlisberger U (2012) A closer look into G protein coupled receptor activation: X-ray crystallography and long-scale molecular dynamics simulations. Curr Med Chem 19(8):1135-1145.
28. Li J, Jonsson AL, Beuming T, Shelley JC, Voth GA (2013) Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor. J Am Chem Soc 135(23):8749-8759.
29. Dror RO, et al. (2011) Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci USA 108(32):13118-13123.
30. Dror RO, et al. (2013) Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503(7475):295-299.
31. Miao Y, Nichols SE, Gasper PM, Metzger VT, McCammon JA (2013) Activation and dynamic network of the M2 muscarinic receptor. Proc Natl Acad Sci USA 110(27):10982-10987.
32. Miao Y, Caliman AD, McCammon JA (2015) Allosteric effects of sodium ion binding on activation of the m3 muscarinic G-protein-coupled receptor. Biophys J 108(7):1796-1806.
33. Miao Y, Nichols SE, McCammon JA (2014) Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics. Phys Chem Chem Phys 16(14):6398-6406.
34. Lin J-H, Perryman AL, Schames JR, McCammon JA (2002) Computational drug design accommodating receptor flexibility: The relaxed complex scheme. J Am Chem Soc 124(20):5632-5633.
35. Amaro RE, Baron R, McCammon JA (2008) An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J Comput Aided Mol Des 22(9):693-705.
36. Shi LM, et al. (2000) Mining and visualizing large anticancer drug discovery databases. J Chem Inf Comput Sci 40(2):367-379.
37. Granier S, Kobilka B (2012) A new era of GPCR structural and chemical biology. Nat Chem Biol 8(8):670-673.
38. Vogel WK, Sheehan DM, Schimerlik MI (1997) Site-directed mutagenesis on the m2 muscarinic acetylcholine receptor: The significance of Tyr403 in the binding of agonists and functional coupling. Mol Pharmacol 52(6):1087-1094.
39. Valant C, Felder CC, Sexton PM, Christopoulos A (2012) Probe dependence in the allosteric modulation of a G protein-coupled receptor: Implications for detection and validation of allosteric ligand effects. Mol Pharmacol 81(1):41-52.
40. Kruse AC, et al. (2014) Muscarinic acetylcholine receptors: Novel opportunities for drug development. Nat Rev Drug Discov 13(7):549-560.
41. Blumensohn R, Razoni G, Shalev A, Munitz H (1986) Bradycardia due to trihexyphenidyl hydrochloride. Drug Intell Clin Pharm 20(10):786-787.
42. Friedman Z, Neumann E (1972) Benzhexol-induced blindness in Parkinson's disease. BMJ 1(5800):605.
43. Harvey RD (2012) Muscarinic receptor agonists and antagonists: Effects on cardiovascular function. Handbook Exp Pharmacol 208(208):299-316.
44. Lazareno S, Birdsall NJ (1995) Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors: Interactions of strychnine and acetylcholine at muscarinic receptors. Mol Pharmacol 48(2):362-378.
45. Levay M, et al. (2013) NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors. J Pharmacol Exp Ther 347(1):69-79.
46. Geisberg CA, Sawyer DB (2010) Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage. Curr Hypertens Rep 12(6):404-410.
47. Chugun A, et al. (2000) Anti-muscarinic actions of mitoxantrone in isolated heart muscles of guinea pigs. Eur J Pharmacol 407(1-2):183-189.
48. Chugun A, et al. (2001) Doxorubicin affects the cardiac muscarinic system in the rat. J Vet Med Sci 63(12):1315-1322.
49. Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG (2012) ZINC: A free tool to discover chemistry for biology. J Chem Inf Model 52(7):1757-1768.
50. Groom CR, Bruno IJ, Lightfoot MP, Ward SC (2016) The Cambridge Structural Database. Acta Crystallogr B Struct Sci Cryst Eng Mater 72(Pt 2):171-179.