Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

Journal of Computer-Aided Molecular Design

Volumn 24, Issue 12, 2010, Pages 971-991

  Kalid, Ori ^a,b   Mense, Martin ^c,h   Fischman, Sharon ^a,i   Shitrit, Alina ^a,k   Bihler, Hermann ^c,j   Ben Zeev, Efrat ^a,k   Schutz, Nili ^a,k   Pedemonte, Nicoletta ^d   Thomas, Philip J ^e   Bridges, Robert J ^f   Wetmore, Diana R ^g,l   Marantz, Yael ^a,m   Senderowitz, Hanoch ^a,n  

^a EPIX Pharmaceuticals Ltd   (Israel)

^b TEL AVIV UNIVERSITY   (Israel)

^c Epix Pharmaceuticals   (United States)

^d ADVANCED BIOTECHNOLOGY CENTER   (Italy)

^e UNIVERSITY OF TEXAS AT DALLAS   (United States)

^f ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE   (United States)

^g Cystic Fibrosis Foundation Therapeutics   (United States)

^h Cystic Fibrosis Foundation Therapeutics   (United States)

ⁱ Biolojic Design LTD   (Israel)

^j CFRx LLC   (United States)

^k Dynamix Pharmaceuticals Ltd   (Israel)

^l Emerald BioStructures   (United States)

^m TEVA PHARMACEUTICALS   (Israel)

ⁿ BAR ILAN UNIVERSITY   (Israel)

more..

Author keywords

CFTR; Chemical chaperones; Correctors; Cystic fibrosis; Docking; F508; Homology modeling; Modulators; Pharmacological chaperones; Potentiators; Structure based virtual screening; Ussing chamber; YFP

Indexed keywords

POTENTIOMETERS (ELECTRIC MEASURING INSTRUMENTS);

CFTR; CHEMICAL CHAPERONE; CORRECTOR; CYSTIC FIBROSIS; DOCKING; HOMOLOGY MODELING; PHARMACOLOGICAL CHAPERON; POTENTIATOR; STRUCTURE-BASED; STRUCTURE-BASED VIRTUAL SCREENING; USSING CHAMBER; VIRTUAL SCREENING; YFP;

BINDING SITES;

NUCLEOTIDE BINDING PROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR;

ARTICLE; BINDING SITE; COMPUTER MODEL; CONTROLLED STUDY; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; MOLECULAR DOCKING; MOLECULAR MODEL; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN STABILITY; PROTEIN STRUCTURE; STRUCTURE ANALYSIS;

EID: 78651264296     PISSN: 0920654X     EISSN: 15734951     Source Type: Journal    
DOI: 10.1007/s10822-010-9390-0     Document Type: Article

References (66)

1. Gadsby DC, Nairn AC (1999) Control of cftr channel gating by phosphorylation and nucleotide hydrolysis. Physiol Rev 79 (1 Suppl): S77-S107
2. Riordan JR (2008) Cftr function and prospects for therapy. Annu Rev Biochem 77:701-726
3. Davis PB (2006) Cystic fibrosis since 1938. Am J Respir Crit Care Med 173(5):475-482
4. Du K, Lukacs GL (2009) Cooperative assembly and misfolding of cftr domains in vivo. Mol Biol Cell 20(7):1903-1915
5. Du K, Sharma M, Lukacs GL (2005) The deltaf508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of cftr. Nat Struct Mol Biol 12(1):17-25
6. Thibodeau PH, Brautigam CA, Machius M, Thomas PJ (2005) Side chain and backbone contributions of phe508 to cftr folding. Nat Struct Mol Biol 12(1):10-16
7. Conn PM, Ulloa-Aguirre A, Ito J, Janovick JA (2007) G proteincoupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59(3):225-250
8. Pedemonte N, Sonawane ND, Taddei A, Hu J, Zegarra-Moran O, Suen YF, Robins LI, Dicus CW, Willenbring D, Nantz MH, Kurth MJ, Galietta LJ, Verkman AS (2005) Phenylglycine and sulfonamide correctors of defective delta f508 and g551d cystic fibrosis transmembrane conductance regulator chloride-channel gating. Mol Pharmacol 67(5):1797-1807. doi:10.1124/mol.105. 010959
9. Becq F (2006) On the discovery and development of cftr chloride channel activators. Curr Pharm des 12(4):471-484
10. Verkman AS, Lukacs GL, Galietta LJ (2006) Cftr chloride channel drug discovery-inhibitors as antidiarrheals and activators for therapy of cystic fibrosis. Curr Pharm des 12(18):2235-2247
11. Springsteel MF, Galietta LJ, Ma T, By K, Berger GO, Yang H, Dicus CW, Choung W, Quan C, Shelat AA, Guy RK, Verkman AS, Kurth MJ, Nantz MH (2003) Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: towards a pharmacophore model for the nucleotide-binding domain. Bioorg Med Chem 11(18):4113-4120
12. Galietta LJ, Springsteel MF, Eda M, Niedzinski EJ, By K, Haddadin MJ, Kurth MJ, Nantz MH, Verkman AS (2001) Novel cftr chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem 276(23):19723-19728
13. Yang H, Shelat AA, Guy RK, Gopinath VS, Ma T, Du K, Lukacs GL, Taddei A, Folli C, Pedemonte N, Galietta LJ, Verkman AS (2003) Nanomolar affinity small molecule correctors of defective delta f508-cftr chloride channel gating. J Biol Chem 278(37):35079-35085
14. Chappe V, Mettey Y, Vierfond JM, Hanrahan JW, Gola M, Verrier B, Becq F (1998) Structural basis for specificity and potency of xanthine derivatives as activators of the cftr chloride channel. Br J Pharmacol 123(4):683-693
15. Ma T, Vetrivel L, Yang H, Pedemonte N, Zegarra-Moran O, Galietta LJ, Verkman AS (2002) High-affinity activators of cystic fibrosis transmembrane conductance regulator (cftr) chloride conductance identified by high-throughput screening. J Biol Chem 277(40):37235-37241
16. Hwang TC, Wang F, Yang IC, Reenstra WW (1997) Genistein potentiates wild-type and delta f508-cftr channel activity. Am J Physiol 273 (3 Pt 1): C988-C998 (Pubitemid 27422179)
17. Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ (1996) Chemical chaperones correct the mutant phenotype of the delta f508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1(2):117-125
18. Haws CM, Nepomuceno IB, Krouse ME, Wakelee H, Law T, Xia Y, Nguyen H, Wine JJ (1996) Delta f508-cftr channels: kinetics, activation by forskolin, and potentiation by xanthines. Am J Physiol 270 (5 Pt 1): C1544-C1555
19. Van Goor F, Straley KS, Cao D, Gonzalez J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PD, Negulescu P (2006) Rescue of deltaf508-cftr trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol 290(6):L1117-L1130
20. Wang Y, Bartlett MC, Loo TW, Clarke DM (2006) Specific rescue of cystic fibrosis transmembrane conductance regulator processing mutants using pharmacological chaperones. Mol Pharmacol 70(1):297-302
21. Wellhauser L, Chiaw PK, Pasyk S, Li C, Ramjeesingh M, Bear CE (2009) A small-molecule modulator interacts directly with deltaphe508-cftr to modify its ATPase activity and conformational stability. Mol Pharmacol 75(6):1430-1438
22. Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ, Verkman AS (2005) Small-molecule correctors of defective deltaf508-cftr cellular processing identified by highthroughput screening. J Clin Invest 115(9):2564-2571
23. Carlile GW, Robert R, Zhang D, Teske KA, Luo Y, Hanrahan JW, Thomas DY (2007) Correctors of protein trafficking defects identified by a novel high-throughput screening assay. Chembiochem 8(9):1012-1020
24. Dormer RL, Harris CM, Clark Z, Pereira MM, Doull IJ, Norez C, Becq F, McPherson MA (2005) Sildenafil (viagra) corrects deltaf508-cftr location in nasal epithelial cells from patients with cystic fibrosis. Thorax 60(1):55-59
25. Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW (2008) Structural analog of sildenafil identified as a novel corrector of the f508del-cftr trafficking defect. Mol Pharmacol 73(2):478-489
26. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug abc transporter. Nature 443(7108):180-185
27. Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV, Riordan JR (2008) Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the cftr 3d structure crucial to assembly and channel function. Proc Natl Acad Sci U S A 105(9):3256-3261
28. Mornon JP, Lehn P, Callebaut I (2008) Atomic model of human cystic fibrosis transmembrane conductance regulator: membranespanning domains and coupling interfaces. Cell Mol Life Sci 65(16):2594-2612
29. Moran O, Galietta LJ, Zegarra-Moran O (2005) Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. Cell Mol Life Sci 62(4):446-460
30. Huang SY, Bolser D, Liu HY, Hwang TC, Zou X (2009) Molecular modeling of the heterodimer of human cftr's nucleotide-binding domains using a protein-protein docking approach. J Mol Graph Model 27(7):822-828
31. Senderowitz H, Fischman S, Kalid O, Sela I, Shitrit A, Strajbl M, Marantz y (2007) Modeling the three-dimensional structure of cftr. Pediatr Pulmonol 54
32. Wang Y, Loo TW, Bartlett MC, Clarke DM (2007) Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (cftr)-processing mutants by binding to the protein. J Biol Chem 282(46):33247-33251
33. Mense M, Vergani P, White DM, Altberg G, Nairn AC, Gadsby DC (2006) In vivo phosphorylation of cftr promotes formation of a nucleotide-binding domain heterodimer. EMBO J 25(20):4728-4739
34. Vergani P, Lockless SW, Nairn AC, Gadsby DC (2005) Cftr channel opening by atp-driven tight dimerization of its nucleotide-binding domains. Nature 433(7028):876-880
35. He L, Aleksandrov AA, Serohijos AW, Hegedus T, Aleksandrov LA, Cui L, Dokholyan NV, Riordan JR (2008) Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (cftr) mediate regulation of channel gating. J Biol Chem 283(39):26383-26390
36. Sybyl. Tripos Inc (1699) Hanley Road, St. Louis, MO 63144
37. Hadida RS, Hazelwood AR, Grootenhuis PDJ, Zhou J (2006) Modulators of atp-binding cassette transporters
38. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49(2):534-553
39. Linsdell P (2005) Location of a common inhibitor binding site in the cytoplasmic vestibule of the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Biol Chem 280(10):8945-8950. doi:10.1074/jbc. M414354200
40. Linsdell P (2006) Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel. Exp Physiol 91(1):123-129. doi:10.1113/expphysiol.2005.031 757
41. Smith SS, Liu X, Zhang ZR, Sun F, Kriewall TE, McCarty NA, Dawson DC (2001) Cftr: covalent and noncovalent modification suggests a role for fixed charges in anion conduction. J Gen Physiol 118(4):407-431
42. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2):377-389
43. Singh OV, Pollard HB, Zeitlin PL (2008) Chemical rescue of deltaf508-cftr mimics genetic repair in cystic fibrosis bronchial epithelial cells. Mol Cell Proteomics 7(6):1099-1110
44. Norez C, Antigny F, Becq F, Vandebrouck C (2006) Maintaining low ca2+ level in the endoplasmic reticulum restores abnormal endogenous f508del-cftr trafficking in airway epithelial cells. Traffic 7(5):562-573
45. Gentzsch M, Chang XB, Cui L, Wu Y, Ozols VV, Choudhury A, Pagano RE, Riordan JR (2004) Endocytic trafficking routes of wild type and deltaf508 cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15(6):2684-2696
46. Galietta LJV, Moran O (2004) Identification of cftr activators and inhibitors: chance or design? Curr Opin Pharmacol 4(5):497-503
47. Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW, Lorimer D, Kearins MC, Conners K, Condon B, Maloney PC, Guggino WB, Hunt JF, Emtage S (2005) Impact of the deltaf508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem 280(2):1346-1353
48. Schrodinger, llc, portland or. Schrodinger, LLC, Portland OR
49. Zaitseva J, Jenewein S, Oswald C, Jumpertz T, Holland IB, Schmitt L (2005) A molecular understanding of the catalytic cycle of the nucleotide-binding domain of the abc transporter hlyb. Biochem Soc Trans 33 (Pt 5):990-995 (Pubitemid 41659097)
50. Shacham S, Marantz Y, Bar-Haim S, Kalid O, Warshaviak D, Avisar N, Inbal B, Heifetz A, Fichman M, Topf M, Naor Z, Noiman S, Becker OM (2004) Predict modeling and in-silico screening for g-protein coupled receptors. Proteins 57(1):51-86
51. Hanekop N, Zaitseva J, Jenewein S, Holland IB, Schmitt L (2006) Molecular insights into the mechanism of atp-hydrolysis by the nbd of the abc-transporter hlyb. FEBS Lett 580(4):1036-1041
52. Koellner G, Kryger G, Millard CB, Silman I, Sussman JL, Steiner T (2000) Active-site gorge and buried water molecules in crystal structures of acetylcholinesterase from torpedo californica. J Mol Biol 296(2):713-735
53. Jones G, Willett P, Glen RC (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245(1):43-53
54. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267(3):727-748
55. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739-1749
56. Hirth BH, Qiao S, Cuff LM, Cochran BM, Pregel MJ, Gregory JS, Sneddon SF, Kane JL Jr (2005) Discovery of 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase cftr mediated chloride transport. Bioorg Med Chem Lett 15(8):2087-2091
57. Bar-Haim S, Aharon A, Ben-Moshe T, Marantz Y, Senderowitz H (2009) Selex-cs: a new consensus scoring algorithm for hit discovery and lead optimization. J Chem Inf Model 49(3):623-633
58. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23 (1-3): 3-25
59. Cerius2 (2008) 4.11 edn. Accelrys, Inc., San Diego
60. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45(12):2615-2623
61. Sela I, Golan G, Strajbl M, Rivenzon-Segal D, Bar-Haim S, Bloch I, Inbal B, Shitrit A, Ben-Zeev E, Fichman M, Markus Y, Marantz Y, Senderowitz H, Kalid O () G protein coupled receptors-in silico drug discovery and design. Curr Top Med Chem 10(6):638-656
62. Discovery studio (2008) Version 2.1 edn. Accelrys, Inc, San Diego
63. Wang R, Wang S (2001) How does consensus scoring work for virtual library screening? An idealized computer experiment. J Chem Inf Comput Sci 41(5):1422-1426
64. Filimonov D, Poroikov V, Borodina Y, Gloriozova T (1999) Chemical similarity assessment through multilevel neighborhoods of atoms: definition and comparison with the other descriptors. J Chem Inf Comput Sci 39(4):666-670
65. Zegarra-Moran O, Romio L, Folli C, Caci E, Becq F, Vierfond JM, Mettey Y, Cabrini G, Fanen P, Galietta LJ (2002) Correction of g551d-cftr transport defect in epithelial monolayers by genistein but not by cpx or mpb-07. Br J Pharmacol 137(4):504-512
66. Gentzsch M, Choudhury A, Chang XB, Pagano RE, Riordan JR (2007) Misassembled mutant deltaf508 cftr in the distal secretory pathway alters cellular lipid trafficking. J Cell Sci 120 (Pt 3):447-455