Structure-based identification of OATP1B1/3 inhibitors

Area of Science:

• Pharmacology
• Drug Metabolism and Transporter Science

Background:

• Drug-drug interactions (DDIs) involving hepatic transporters organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can lead to significant clinical issues.
• Early identification of OATP1B-mediated DDIs is essential to prevent late-stage drug development failures.

Purpose of the Study:

• To develop and validate high-throughput in vitro and in silico methods for predicting OATP1B1 and OATP1B3 inhibition.
• To identify novel inhibitors and understand structure-activity relationships for OATP1B subfamily inhibition.

Main Methods:

• Developed a high-throughput in vitro assay using OATP1B1/1B3-transfected cells to screen 2000 compounds for inhibition of sodium fluorescein uptake.
• Determined concentration-dependent inhibition and inhibition constants (Ki) for identified inhibitors.
• Created a proteochemometrics-based in silico model using in vitro data to predict OATP1B inhibitors.

Main Results:

• Identified 212 OATP1B1 and 139 OATP1B3 inhibitors at 10 µM.
• Determined Ki values for 69 compounds, ranging from 0.06 to 6.5 µM.
• The in silico model achieved 86% specificity and 78% sensitivity, with prospective validation showing 80% (OATP1B1) and 74% (OATP1B3) correct classification.

Conclusions:

• The developed in vitro and in silico methods are effective for early-stage prediction of OATP1B1 and OATP1B3 inhibition.
• These predictive tools can aid in de-risking drug candidates by identifying potential DDIs early in development.
• Physicochemical properties and substructures associated with OATP1B inhibition were identified, contributing to model development.