Novel cGMP efflux inhibitors identified by virtual ligand screening (VLS) and confirmed by experimental studies

Journal of Medicinal Chemistry

Volumn 55, Issue 7, 2012, Pages 3049-3057

  Sager, Georg ^a   Ørvoll, Elin Ø ^a   Lysaa, Roy A ^a   Kufareva, Irina ^b   Abagyan, Ruben ^b   Ravna, Aina W ^a  

^a UNIVERSITY OF TROMSØ   (Norway)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [[2 BIS(2 HYDROXYETHYL)AMINO] 4,8 DI(PIPERIDIN 1 YL)PYRIMIDO[5, 4 D]PYRIMIDIN 6 YL] (2 HYDROXYETHYL)AMINO]ETHANOL; 4 ETHOXY 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLO(4,3 D)PYRIMIDIN 5 YL] N [3 (1 METHYLPYRROIDIN 2 YL)PYRIDIN 2 YL]BENZENESULFONAMIDE; 4 ETHOXY N (2 HYDROXYETHYL) 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLOL(4,3 D)PYRIMIDIN 5 YL]BENZENESULFONAMIDE; 4 ETHOXY N (2 HYDROXYETHYL) N METHYL 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLOL(4,3 D)PYRIMIDIN 5 YL]BENZENESULFONAMIDE; 4 ETHOXY N METHYL 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLO(4,3 D)PYRIMIDIN 5 YL]BENZENESULFONAMIDE; 4 ETHOXY N,N DIETHYL 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLO(4,3 D)PYRIMIDIN 5 YL]BENZENESULFONAMIDE; 4 ETHOXY N,N DIMETHYL 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLO(4, 3 D)PYRIMIDIN 5 YL]BENZENSULFONAMIDE; 5 (2 ETHOXY 5 PIPERIDIN 1 YLSULFONYLPHENYL) 1 METHYL 3 PROPYL 4H PYRAZOLO(4,3 D)PYRIMIDIN 7 ONE; 5 [5 (AZEPAN 1 YLSULFONYL) 2 ETHOXYPHENYL] 1 METHYL 3 PROPYL 4H PYRAZOLO (4,3 D)PYRIMIDIN 7 ONE; 5 [[3 [3 TERT BUTYL 1 METHYL 7 OXO 4H PYRAZOLO(4,3 D)PYRIMIDIN 5 YL]PHENYL]SULFONYLAMINO] 2 HYDROXYBENZOIC ACID; ABC TRANSPORTER; CYCLIC GMP; CYCLIC GMP DEPENDENT PROTEIN KINASE INHIBITOR; DIPYRIDAMOLE; N BENZYL 4 ETHOXY 3 [1 METHYL 7 OXO 3 PROPYL 4H PYRAZOLO(4,3 D)PYRIMIDIN 5 YL]BENZENESULFONAMIDE; SILDENAFIL; UNCLASSIFIED DRUG; ZAPRINAST;

ARTICLE; BINDING KINETICS; BINDING SITE; BIOLOGICAL ACTIVITY; COMPETITIVE INHIBITION; CONCENTRATION RESPONSE; DRUG CONFORMATION; DRUG POTENCY; DRUG SCREENING; EXPERIMENTAL STUDY; HYDROGEN BOND; IN VITRO STUDY; MOLECULAR DOCKING; MOLECULAR MODEL; PROTEIN TRANSPORT; STRUCTURE ACTIVITY RELATION; VIRTUAL LIGAND SCREENING;

AMINO ACID SEQUENCE; ANIMALS; CYCLIC GMP; DATABASES, FACTUAL; ERYTHROCYTE MEMBRANE; HUMANS; LIGANDS; MICE; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; PIPERAZINES; PROTEIN BINDING; PURINES; SEQUENCE ALIGNMENT; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 84859796831     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2014666     Document Type: Article

References (42)

1. Luesley, D. M.; Blackledge, G. R.; Chan, K. K.; Newton, J. R. Random urinary cyclic 3a,5a guanosine monophosphate in epithelial ovarian cancer: relation to other prognostic variables and to survival Br. J. Obstet. Gynaecol. 1986, 93, 380-385
2. Orbo, A.; Jaeger, R.; Sager, G. Urinary levels of cyclic guanosine monophosphate (cGMP) in patients with cancer of the uterine cervix: a valuable prognostic factor of clinical outcome? Eur. J. Cancer 1998, 34, 1460-1462
3. Peracchi, M.; Bamonti-Catena, F.; Lombardi, L.; Toschi, V.; Bareggi, B.; Cortelezzi, A.; Maiolo, A. T.; Polli, E. E. Plasma cyclic nucleotide levels in monitoring acute leukemia patients Cancer Detect. Prev. 1985, 8, 291-295
4. Turner, G. A.; Greggi, S.; Guthrie, D.; Benedetti Panici, P.; Ellis, R. D.; Scambia, G.; Mancuso, S. Monitoring ovarian cancer using urine cyclic GMP. A two-centre study Eur. J. Gynaecol. Oncol. 1990, 11, 421-427
5. Jedlitschky, G.; Burchell, B.; Keppler, D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides J. Biol. Chem. 2000, 275, 30069-30074
6. Pilz, R. B.; Broderick, K. E. Role of cyclic GMP in gene regulation Front. Biosci. 2005, 10, 1239-1268
7. Saier, M. H., Jr. A functional-phylogenetic classification system for transmembrane solute transporters Microbiol. Mol. Biol. Rev. 2000, 64, 354-411
8. Dean, M.; Rzhetsky, A.; Allikmets, R. The human ATP-binding cassette (ABC) transporter superfamily Genome Res. 2001, 11, 1156-1166
9. Ravna, A. W.; Sylte, I.; Sager, G. Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5) Theor. Biol. Med. Modell. 2007, 4, 33
10. Ravna, A. W.; Sylte, I.; Sager, G. Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure Theor. Biol. Med. Modell. 2009, 6, 20
11. Ravna, A. W.; Sager, G. Molecular model of the outward facing state of the human multidrug resistance protein 4 (MRP4/ABCC4) Bioorg. Med. Chem. Lett. 2008, 18, 3481-3483
12. Ravna, A. W.; Sylte, I.; Sager, G. A molecular model of a putative substrate releasing conformation of multidrug resistance protein 5 (MRP5) Eur. J. Med. Chem. 2008, 43, 2557-2567
13. Dawson, R. J.; Locher, K. P. Structure of a bacterial multidrug ABC transporter Nature 2006, 443, 180-185
14. Ward, A.; Reyes, C. L.; Yu, J.; Roth, C. B.; Chang, G. Flexibility in the ABC transporter MsbA: alternating access with a twist Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 19005-19010
15. Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding Science 2009, 323, 1718-1722
16. + symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function Mol. Pharmacol. 2006, 70, 1630-1642
17. Hibert, M. F.; Trumpp-Kallmeyer, S.; Bruinvels, A.; Hoflack, J. Three-dimensional models of neurotransmitter G-binding protein-coupled receptors Mol. Pharmacol. 1991, 40, 8-15
18. Loo, T. W.; Bartlett, M. C.; Clarke, D. M. Human P-glycoprotein is active when the two halves are clamped together in the closed conformation Biochem. Biophys. Res. Commun. 2010, 395, 436-440
19. Verhalen, B.; Wilkens, S. P-glycoprotein retains drug-stimulated ATPase activity upon covalent linkage of the two nucleotide binding domains at their C-terminal ends J. Biol. Chem. 2011, 286, 10476-10482
20. Loo, T. W.; Bartlett, M. C.; Clarke, D. M. Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding J. Biol. Chem. 2003, 278, 13603-13606
21. Abagyan, R.; Totrov, M.; Kuznetsov, D. N. ICM: a new method for protein modeling and design. Applications to docking and structure prediction from the distorted native comformation J. Comput. Chem. 1994, 15, 488-506
22. Cavasotto, C. N.; Orry, A. J.; Murgolo, N. J.; Czarniecki, M. F.; Kocsi, S. A.; Hawes, B. E.; O'Neill, K. A.; Hine, H.; Burton, M. S.; Voigt, J. H.; Abagyan, R. A.; Bayne, M. L.; Monsma, F. J., Jr. Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening J. Med. Chem. 2008, 51, 581-588
23. Katritch, V.; Byrd, C. M.; Tseitin, V.; Dai, D.; Raush, E.; Totrov, M.; Abagyan, R.; Jordan, R.; Hruby, D. E. Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches J. Comput.-Aided Mol. Des. 2007, 21, 549-558
24. Zhang, K. Y.; Card, G. L.; Suzuki, Y.; Artis, D. R.; Fong, D.; Gillette, S.; Hsieh, D.; Neiman, J.; West, B. L.; Zhang, C.; Milburn, M. V.; Kim, S. H.; Schlessinger, J.; Bollag, G. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases Mol. Cell 2004, 15, 279-286
25. Boadu, E.; Sager, G. ATPase activity and transport by a cGMP transporter in human erythrocyte ghosts and proteoliposome-reconstituted membrane extracts Biochim. Biophys. Acta 2000, 1509, 467-474
26. Sager, G.; Ravna, A. W. Cellular efflux of cAMP and cGMP: a question about selectivity Mini-Rev. Med. Chem. 2009, 9, 1009-1013
27. Sundkvist, E.; Jaeger, R.; Sager, G. Pharmacological characterization of the ATP-dependent low K(m) guanosine 3a,5a-cyclic monophosphate (cGMP) transporter in human erythrocytes Biochem. Pharmacol. 2002, 63, 945-949
28. Loo, T. W.; Bartlett, M. C.; Clarke, D. M. Transmembrane segment 1 of human P-glycoprotein contributes to the drug-binding pocket Biochem. J. 2006, 396, 537-545
29. Wu, C. P.; Calcagno, A. M.; Ambudkar, S. V. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies Curr. Mol. Pharmacol. 2008, 1, 93-105
30. Shi, Z.; Tiwari, A. K.; Patel, A. S.; Fu, L. W.; Chen, Z. S. Roles of sildenafil in enhancing drug sensitivity in cancer Cancer Res. 2011, 71, 3735-3738
31. Kulkarni, S. K.; Patil, C. S. Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects Methods Find. Exp. Clin. Pharmacol. 2004, 26, 789-799
32. Notredame, C.; Higgins, D. G.; Heringa, J. T-Coffee: a novel method for fast and accurate multiple sequence alignment J. Mol. Biol. 2000, 302, 205-217
33. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank Nucleic Acids Res. 2000, 28, 235-242
34. Abagyan, R.; Totrov, M. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins J. Mol. Biol. 1994, 235, 983-1002
35. Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Pearlman, D. A.; Crowley, M.; Walker, R. C.; Zhang, W.; Wang, B.; Hayik, A.; Roitberg, A.; Seabra, G.; Wong, K.; Paesani, F.; Wu, X.; Brozell, S.; Tsui, V.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Mathews, D. H.; Schafmeister, C.; Ross, W. S.; Kollman, P. A. AMBER 9; University of California: San Francisco, CA, 2006.
36. Laskoswki, R. A.; MacArthur, M. W.; Moss, D. S.; Thorton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291
37. Hooft, R. W.; Vriend, G.; Sander, C.; Abola, E. E. Errors in protein structures Nature 1996, 381, 272
38. Colovos, C.; Yeates, T. O. Verification of protein structures: patterns of nonbonded atomic interactions Protein Sci. 1993, 2, 1511-1519
39. Abagyan, R.; Kufareva, I. The flexible pocketome engine for structural chemogenomics Methods Mol. Biol. 2009, 575, 249-279
40. Bottegoni, G.; Kufareva, I.; Totrov, M.; Abagyan, R. Four-dimensional docking: a fast and accurate account of discrete receptor flexibility in ligand docking J. Med. Chem. 2009, 52, 397-406
41. Steck, T. L.; Weinstein, R. S.; Straus, J. H.; Wallach, D. F. Inside-out red cell membrane vesicles: preparation and purification Science 1970, 168, 255-257
42. Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction Biochem. Pharmacol. 1973, 22, 3099-3108