title: Structure-based identification of OATP1B1/3 inhibitors.
abstract: Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: De Bruyn
authors.forename: Gerard J P
authors.initials: GJ
authors.lastname: van Westen
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Peter
authors.initials: P
authors.lastname: de Witte
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Augustijns
authors.forename: Pieter P
authors.initials: PP
authors.lastname: Annaert
mesh_terms: D000465:Algorithms; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D027361:Organic Anion Transporters; D054852:Small Molecule Libraries