Exploring the structure–activity relationships of ABCC2 modulators using a screening approach. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Wissel, Gloria; Kudryavtsev, Pavel; Ghemtio, Leo; Tammela, Päivi; Wipf, Peter; Yliperttula, Marjo; Finel, Moshe; Urtti, Arto; Kidron, Heidi; Xhaard, Henri
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3513
• Page End: 3525
• Publication Date: 2015-07-01
• Subjects: WRJCENKZISEXPF-UHFFFAOYSA-N; ABC ATP-binding cassette -- CDCF 5(6)-carboxy-2′, 7′-dichlorofluorescein -- EG β-estradiol 17-(β-d-glucuronide) -- MRP2 Multidrug Resistance associated Protein 2 -- SARs structure activity relationships -- SVM support vector machine; ABCC2 -- ABC transporter -- CDCF -- Estradiol glucuronide -- Efflux -- Inhibitor -- Membrane vesicles -- Modulator -- MRP2 -- Sf9 -- Stimulator -- Structure–activity relationships -- SVM modelling -- Transport -- Transport assay; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.029
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: ABCC2 is a transporter with key influence on liver and kidney pharmacokinetics. In order to explore the structure–activity relationships of compounds that modulate ABCC2, and by doing so gain insights into drug–drug interactions, we screened a library of 432 compounds for modulators of radiolabeled β-estradiol 17-(β-d -glucuronide) (EG) and fluorescent 5(6)-carboxy-2′, 7′-dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80 μM, dose–response curves were used to investigate in detail 86 compounds, identifying 16 low μM inhibitors and providing data about the structure–activity relationships in four series containing 19, 24, 10, and eight analogues. Measurements with the CDCF probe were consistently more robust than for the EG probe. Only one compound was clearly probe-selective with a 50-fold difference in the IC50 s obtained by the two assays. We built 24 classification models using the SVM and fused-XY Kohonen methods, revealing molecular descriptors related to number of rings, solubility and lipophilicity as important to distinguish inhibitors from inactive compounds. This study is to the best of our knowledge the first to provide details about structure–activity relationships in ABCC2 modulation.