Computational Modeling of OATP1B1 Inhibitors

Authors: Lawless M, Clark RD, Bolger MB, Woltosz WS
Conference: SOT
Keywords: acute systemic toxicity, ADMET, ANNE, artificial neural network ensembles (ANNE), OATPs, Organic anion-transporting polypeptides (OATPs)
Software: ADMET Predictor®
Division: Simulations Plus

Introduction

  • Organic Anion Transporting Polypeptide 1B1 (OATP1B1)
  • Highly expressed uptake transporter in human hepatocytes
  • Interacts predominantly with negatively charged species
  • Inhibited by cyclosporine A and rifampicin
  • Important in drug-drug interactions (DDIs) because inhibition by one drug may lead to systemic toxicity due to elevated levels in the blood or subtherapeutic levels of another in the liver
  • Considered one of the seven most important transporters in drug disposition by the International Transporter Consortium

An artificial neural network ensemble (ANNE) classification model was created from OATP1B1 inhibition data for 336 compounds. The model was used to predict OATP1B1 inhibition of a subset of about 2,300 compounds from the World Drug Index (WDI).

SOT 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phoenix, AZ

By Michael Lawless, Robert D. Clark, Michael Bolger, and Walter Woltosz