Exploring the structure-activity relationships of ABCC2 modulators using a screening approach.

Area of Science:

• Pharmacology and Toxicology
• Biochemistry
• Medicinal Chemistry

Background:

• The ABCC2 transporter significantly impacts drug pharmacokinetics in the liver and kidneys.
• Understanding ABCC2 modulation is crucial for predicting and mitigating drug-drug interactions.

Purpose of the Study:

• To explore structure-activity relationships (SAR) of compounds modulating ABCC2.
• To identify novel ABCC2 inhibitors and gain insights into their mechanisms.

Main Methods:

• Screening of 432 compounds using radiolabeled β-estradiol 17-(β-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) transport assays in membrane vesicles.
• Dose-response analysis of 86 selected compounds to determine IC50 values.
• Development of 24 classification models using Support Vector Machine (SVM) and fused-XY Kohonen methods.

Main Results:

• Identified 16 low micromolar inhibitors of ABCC2.
• Detailed SAR data were generated for four compound series.
• CDCF probe measurements were more robust than EG probe measurements; one compound showed probe selectivity.
• Molecular descriptors related to ring count, solubility, and lipophilicity were identified as key for distinguishing inhibitors.

Conclusions:

• This research provides the first detailed SAR for ABCC2 modulators.
• The findings contribute to a better understanding of ABCC2 function and drug interactions.
• The identified molecular descriptors can guide future drug design targeting ABCC2.