Computational Discovery and Experimental Validation of Inhibitors of the Human Intestinal Transporter OATP2B1

Human organic anion
transporters (OATPs) are vital for the uptake
and efflux of drugs and endogenous compounds. Current identification
of inhibitors of these transporters is based on experimental screening.
Virtual screening remains a challenge due to a lack of experimental
three-dimensional protein structures. Here, we describe a workflow
to identify inhibitors of the OATP2B1 transporter in the DrugBank
library of over 5,000 drugs and druglike molecules. OATP member 2B1
transporter is highly expressed in the intestine, where it participates
in oral absorption of drugs. Predictions from a Random forest classifier,
prioritized by docking against multiple comparative protein structure
models of OATP2B1, indicated that 33 of the 5,000 compounds were putative
inhibitors of OATP2B1. Ten predicted inhibitors that are prescription
drugs were tested experimentally in cells overexpressing the OATP2B1
transporter. Three of these ten were validated as potent inhibitors
of estrone-3-sulfate uptake (defined as more than 50% inhibition at
20 μM) and tested in multiple concentrations to determine exact
IC50. The IC50 values of bicalutamide, ticagrelor,
and meloxicam suggest that they might inhibit intestinal OATP2B1 at
clinically relevant concentrations and therefore modulate the absorption
of other concomitantly administered drugs.