Using structural and mechanistic information to design novel inhibitors/Substrates of P-Glycoprotein

Current Topics in Medicinal Chemistry

Volumn 10, Issue 17, 2010, Pages 1769-1774

  Klepsch, Freya ^a   Stockner, Thomas ^b   Erker, Thomas ^a   Müller, Markus ^b   Chiba, Peter ^b   Ecker, Gerhard F ^a  

^a UNIVERSITY OF VIENNA   (Austria)

^b MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

ABC; Atp binding cassette; Bbb; BCRP; Blood brain barrier; Breast cancer related protein; Central nervous system; CNS; CPPI; Cyclic peptide p glycoprotein inhibitor; CYP; Cytochrome p450 3a4; DAT; Dopamine transporter; MDR; Multidrug resistance; NBD; NET; Norepinephrine transporter; Nucleotide binding domain; P glycoprotein; P gp; PET; Plif; Positron emission tomography; Protein ligand interaction fingerprints; SAR structure activity relationship; Serotonine reuptake transporter; SERT; Single photon emission computed tomography; SPECT; TMD; Transmembrane domain

Indexed keywords

CYTOCHROME P450 3A4; DAUNORUBICIN; ELACRIDAR; GLYCOPROTEIN P; GLYCOPROTEIN P INHIBITOR; LANIQUIDAR; LOPERAMIDE; MULTIDRUG RESISTANCE PROTEIN 1; PACLITAXEL; QUINAZOLINONE DERIVATIVE; TARIQUIDAR; TRACER; VERAPAMIL;

ARTICLE; DRUG DESIGN; DRUG TRANSPORT; HYDROLYSIS; LIGAND BINDING; MOLECULAR DOCKING; MULTIDRUG RESISTANCE; NONHUMAN; PHARMACOPHORE; POSITRON EMISSION TOMOGRAPHY; SEQUENCE HOMOLOGY; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; STRUCTURAL GENOMICS; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; BINDING SITES; BIOLOGICAL TRANSPORT; DRUG DESIGN; HUMANS; MOLECULAR STRUCTURE; P-GLYCOPROTEIN;

EID: 77957982101     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802610792928004     Document Type: Article

References (48)

1. Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2002, 2(1), 48-58.
2. Ecker, G.F.; Chiba, P. In: Transporters as Drug Carriers, G. F. Ecker and P. Chiba, Eds.; Wiley-VCH: Weinheim, 2009; Vol. 44, pp. 349-359.
3. Juliano, R.L.; Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta, 1976, 455(1), 152-162.
4. Goldberg, H.; Ling, V.; Wong, P.Y.; Skorecki, K. Reduced cyclosporin accumulation in multidrug-resistant cells. Biochem. Biophys. Res. Commun., 1988, 152(2), 552-558.
5. Szakacs, G.; Varadi, A.; Ozvegy-Laczka, C.; Sarkadi, B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov. Today, 2008, 13(9-10), 379-393.
6. Benet, L.Z.; Cummins, C.L. The drug efflux-metabolism alliance: biochemical aspects. Adv. Drug Deliv. Rev., 2001, 50 (Suppl 1), S3-11.
7. Raderer, M.; Scheithauer, W. Clinical trials of agents that reverse multidrug resistance. A literature review. Cancer, 1993, 72(12), 3553-3563.
8. Kannan, P.; John, C.; Zoghbi, S.S.; Halldin, C.; Gottesman, M.M.; Innis, R.B.; Hall, M.D. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin. Pharmacol. Ther., 2009, 86(4), 368-377.
9. Sharma, V. Radiopharmaceuticals for assessment of multidrug resistance P-glycoprotein-mediated drug transport activity. Bio-conjug. Chem., 2004, 15(6), 1464-1474.
10. Elsinga, P.H.; Hendrikse, N.H.; Bart, J.; Vaalburg, W.; van Waarde, A. PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr. Pharm. Des., 2004, 10(13), 1493-1503.
11. Bauer, F.; Mairinger, S.; Dörner, B.; Kuntner, C.; Stundner, G.; Bankstahl, J.P.; Wanek, T.; Stanek, J.; Müller, M.; Langer, O.; Erker, T. Synthesis and PET evaluation of the radiolabelled P-glycoprotein inhibitor [11C]tariquidar. Eur. J. Nucl. Med. Mol. Imaging, 2009, 36, 222.
12. Dörner, B.; Kuntner, C.; Bankstahl, J.P.; Bankstahl, M.; Stanek, J.; Wanek, T.; Stundner, G.; Mairinger, S.; Loscher, W.; Muller, M.; Langer, O.; Erker, T. Synthesis and small-animal positron emission tomography evaluation of [11C]-elacridar as a radiotracer to assess the distribution of P-glycoprotein at the blood-brain barrier. J. Med. Chem., 2009, 52(19), 6073-6082.
13. Luurtsema, G.; Schuit, R.C.; Klok, R.P.; Verbeek, J.; Leysen, J.E.; Lammertsma, A.A.; Windhorst, A.D. Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats. Nucl. Med. Biol., 2009, 36(6), 643-649.
14. van Waarde, A.; Ramakrishnan, N.K.; Rybczynska, A.A.; Elsinga, P.H.; Berardi, F.; de Jong, J.R.; Kwizera, C.; Perrone, R.; Cantore, M.; Sijbesma, J.W.; Dierckx, R.A.; Colabufo, N.A. Synthesis and preclinical evaluation of novel PET probes for P-glycoprotein function and expression. J. Med. Chem., 2009, 52(14), 4524-4532.
15. Eckelman, W.C.; Mathis, C.A. Targeting proteins in vivo: in vitro guidelines. Nucl. Med. Biol., 2006, 33(2), 161-164.
16. Miller, D.S.; Bauer, B.; Hartz, A.M. Modulation of P-glyco-protein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol. Rev., 2008, 60(2), 196-209.
17. Broccatelli, F.; Carosati, E.; Cruciani, G.; Oprea, T.I. Transportermediated efflux influences CNS side effects: ABCB1, from antitarget to target. Mol. Inf., 2010, 29, 16-26.
18. Demel, M.A.; Kramer, O.; Ettmayer, P.; Haaksma, E.E.; Ecker, G.F. Predicting ligand interactions with ABC transporters in ADME. Chem. Biodivers, 2009, 6(11), 1960-1969.
19. 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(5922), 1718-1722.
20. Seeger, M.A.; van Veen, H.W. Molecular basis of multidrug transport by ABC transporters. Biochim. Biophys. Acta, 2009, 1794(5), 725-737.
21. Chang, G.; Roth, C.B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science, 2001, 293(5536), 1793-1800.
22. Chang, G. Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation. J. Mol. Biol., 2003, 330(2), 419-430.
23. Reyes, C.L.; Chang, G. Structure of the ABC transporter MsbA in complex with ADP.vanadate and lipopolysaccharide. Science, 2005, 308(5724), 1028-1031.
24. Dawson, R.J.; Locher, K.P. Structure of a bacterial multidrug ABC transporter. Nature, 2006, 443(7108), 180-185.
25. Becker, J.P.; Depret, G.; Van Bambeke, F.; Tulkens, P.M.; Prevost, M. Molecular models of human P-glycoprotein in two different catalytic states. BMC Struct. Biol., 2009, 9(3).
26. Globisch, C.; Pajeva, I.K.; Wiese, M. Identification of putative binding sites of P-glycoprotein based on its homology model. Chem. Med.Chem., 2008, 3(2), 280-295.
27. Stockner, T.; de Vries, S.J.; Bonvin, A.M.; Ecker, G.F.; Chiba, P. Data-driven homology modelling of P-glycoprotein in the ATP- bound state indicates flexibility of the transmembrane domains. FEBS J., 2009, 276(4), 964-972.
28. O'Mara, M.L.; Tieleman, D.P. P-glycoprotein models of the apo and ATP-bound states based on homology with Sav1866 and MalK. FEBS Lett., 2007, 581(22), 4217-4222.
29. 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. USA, 2007, 104(48), 19005-19010.
30. Pajeva, I.K.; Globisch, C.; Wiese, M. Combined pharmacophore modeling, docking, and 3D QSAR studies of ABCB1 and ABCC1 transporter inhibitors. Chem. Med. Chem., 2009, 4(11), 1883-1896.
31. Loo, T.W.; Clarke, D.M. The transmembrane domains of the human multidrug resistance P-glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface. J. Biol. Chem., 1999, 274(35), 24759-24765.
32. Loo, T.W.; Clarke, D.M. Mutational analysis of ABC proteins. Arch. Biochem. Biophys., 2008, 476(1), 51-64.
33. Shilling, R.A.; Venter, H.; Velamakanni, S.; Bapna, A.; Woebking, B.; Shahi, S.; van Veen, H.W. New light on multidrug binding by an ATP-binding-cassette transporter. Trends Pharmacol. Sci., 2006, 27(4), 195-203.
34. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Transmembrane segment 7 of human P-glycoprotein forms part of the drug-binding pocket. Biochem. J., 2006, 399(2), 351-359.
35. Loo, T.W.; Clarke, D.M. Identification of residues in the drug-binding site of human P-glycoprotein using a thiol-reactive substrate. J. Biol. Chem., 1997, 272(51), 31945-31948.
36. Klepsch, F.; Chiba, P.; Ecker, G.F. Docking studies to identify the binding mode of propafenones to p-glycoprotein. Drugs Future, 2009, 34(Suppl A), 164.
37. Szabo, K.; Bakos, E.; Welker, E.; Muller, M.; Goodfellow, H.R.; Higgins, C.F.; Varadi, A.; Sarkadi, B. Phosphorylation site mutations in the human multidrug transporter modulate its drug-stimulated ATPase activity. J. Biol. Chem., 1997, 272(37), 23165-23171.
38. Schumacher, M.A.; Miller, M.C.; Brennan, R.G. Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein. EMBO J., 2004, 23(15), 2923-2930.
39. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resis-tance P-glycoprotein. J. Biol. Chem., 2003, 278(41), 39706-39710.
40. Richter, L.; Ernst, M.; Sieghart, W.; Ecker, G.F. Combining multiple apporaches in pose evaluation - Application to the GABAA receptor. Sci. Pharm., 2009, 77(1), 181.
41. Weissensteiner, R.; Sitte, H.H.; Freissmuth, M.; Ecker, G.F. Docking of substrates and inhibitors into new models of neurotransmitter: Sodium symporter. Sci. Pharm., 2009, 77(1), 205.
42. Szakacs, G.; Annereau, J.P.; Lababidi, S.; Shankavaram, U.; Arciello, A.; Bussey, K.J.; Reinhold, W.; Guo, Y.; Kruh, G.D.; Reimers, M.; Weinstein, J.N.; Gottesman, M.M. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell, 2004, 6(2), 129-137.
43. Klepsch, F.; Jabeen, I.; Chiba, P.; Ecker, G.F. Pharmacoinformatic approaches to design natural product type ligands of ABC- transporters. Curr. Pharm. Des., 2010, 16(15), 1712-1752.
44. Hegedus, C.; Ozvegy-Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br. J. Pharmacol., 2009, 158(4), 1153-1164.
45. Chene, P. The ATPases: a new family for a family-based drug design approach. Expert Opin. Ther. Targets, 2003, 7(3), 453-461.
46. Copeland, R.A.; Pompliano, D.L.; Meek, T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov., 2006, 5(9), 730-739.
47. Ernst, R.; Kueppers, P.; Stindt, J.; Kuchler, K.; Schmitt, L. Multidrug efflux pumps: substrate selection in ATP-binding cassette multidrug efflux pumps--first come, first served? FEBS J., 2010, 277(3), 540-549.
48. Pajeva, I.K.; Globisch, C.; Wiese, M. Comparison of the inward- and outward-open homology models and ligand binding of human P-glycoprotein. FEBS J., 2009, 276(23), 7016-7026.