Technical pitfalls and improvements for high-speed screening and QSAR analysis to predict inhibitors of the human bile salt export pump (ABCB11/BSEP).
Drug-induced hepatotoxicity is one of the major problems encountered in drug discovery and development. Selection of a candidate compound for pre-clinical studies in the drug discovery process is a critical step that can determine the speed and expenditure of clinical development. Because inhibition of human adenosine triphosphate-binding cassette transporter ABCB11 (SPGP/bile salt export pump) has severe consequences, which include intrahepatic cholestasis and hepatotoxicity, resulting from exposure to toxic xenobiotics or drug interactions, in vitro screening methods are necessary for quantifying and characterizing the inhibition of ABCB11. In line with such initiatives, we developed methods for in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis to investigate the interaction of ABCB11 with a variety of compounds. We identified one set of chemical fragmentation codes closely linked with inhibition of ABCB11. Furthermore, the high-speed screening method enables us to analyze the kinetics of ABCB11-inhibition by test compounds and to distinguish competitive and non-competitive inhibitors. Troglitazone and novobiocin were found to be competitive inhibitors to taurocholate, whereas porphyrins were non-competitive inhibitors. Kinetics-based classification of inhibitors is considered important to improve the accuracy of our QSAR analysis. The present mini-review addresses technical pitfalls and improvements for high-speed screening and QSAR analysis in the ABCB11 inhibition study.
Saito
Hikaru
H
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta, Yokohama, Japan.
Osumi
Masako
M
Hirano
Hiroyuki
H
Shin
Wangsoo
W
Nakamura
Ryota
R
Ishikawa
Toshihisa
T
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D002839:Chromans / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D011786:Quality Control; D021281:Quantitative Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002839:Chromans; D045162:Thiazolidinediones; D000077288:Troglitazone
Mol Pharmacol. 2001 Mar;59(3):627-35
11179459
Cancer Res. 1995 May 15;55(10):2029-34
7538046
Nat Biotechnol. 2000 Feb;18(2):168-71
10657122
Mol Pharm. 2006 May-Jun;3(3):252-65
16749857
Annu Rev Pharmacol Toxicol. 2005;45:177-202
15822174
J Gen Virol. 1997 Dec;78 ( Pt 12):3081-9
9400956
Gastroenterology. 2002 Nov;123(5):1659-66
12404240
Clin Pharmacol Ther. 2001 Apr;69(4):223-31
11309550
Biol Pharm Bull. 2004 Jul;27(7):939-48
15256718
Toxicology. 2001 Oct 5;167(1):83-98
11557132
Front Biosci (Landmark Ed). 2009 Jan 01;14:3523-35
19273290
J Pharmacol Exp Ther. 2006 Jun;317(3):1114-24
16489126
Pharmacogenetics. 2004 Feb;14(2):91-102
15077010
Physiol Rev. 2003 Apr;83(2):633-71
12663868
Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G734-8
12684208
Hepatology. 1991 Sep;14(3):551-66
1874500
J Virol. 1992 Nov;66(11):6829-35
1404622
J Clin Invest. 2002 Oct;110(7):965-72
12370274
Nat Genet. 1998 Nov;20(3):233-8
9806540
Glycobiology. 2003 Apr;13(4):17R-27R
12626396
J Biol Chem. 1998 Apr 17;273(16):10046-50
9545351
Virology. 1998 Jun 20;246(1):1-23
9656989
J Electron Microsc (Tokyo). 1989;38(6):457-68
2516868
Annu Rev Biochem. 2002;71:537-92
12045106
Gastroenterology. 2004 Jan;126(1):322-42
14699511
Pflugers Arch. 2004 Nov;449(2):123-31
15578267
Biochemistry. 2007 Jul 3;46(26):7678-93
17559192
Science. 2009 Mar 27;323(5922):1718-22
19325113
Chem Res Toxicol. 2003 Jun;16(6):679-87
12807350
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2011-6
11172067
Drug Metab Pharmacokinet. 2004 Feb;19(1):1-14
15499164
Virology. 1998 Mar 30;243(1):167-77
9527926
J Clin Invest. 1978 Apr;61(4):998-1026
659586
Methods Enzymol. 2005;400:485-510
16399366
Drug Metab Pharmacokinet. 2006 Oct;21(5):347-56
17072088
J Electron Microsc (Tokyo). 1995 Aug;44(4):198-206
8568444