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Novel Inhibitors of Human Organic Cation/Carnitine Transporter (hOCTN2) via Computational Modeling and In Vitro Testing

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Abstract

Purpose

The objective was to elucidate the inhibition requirements of the human organic cation/carnitine transporter (hOCTN2).

Methods

Twenty-seven drugs were screened initially for their potential to inhibit uptake of l-carnitine into a stably transfected hOCTN2-MDCK cell monolayer. A HipHop common features pharmacophore was developed and used to search a drug database. Fifty-three drugs, including some not predicted to be inhibitors, were selected and screened in vitro.

Results

A common features pharmacophore was derived from initial screening data and consisted of three hydrophobic features and a positive ionizable feature. Among the 33 tested drugs that were predicted to map to the pharmacophore, 27 inhibited hOCTN2 in vitro (40% or less l-carnitine uptake from 2.5 μM l-carnitine solution in presence of 500 μM drug, compared to l-carnitine uptake without drug present). Hence, the pharmacophore accurately prioritized compounds for testing. K i measurements showed low micromolar inhibitors belonged to diverse therapeutic classes of drugs, including many not previously known to inhibit hOCTN2. Compounds were more likely to cause rhabdomyolysis if the C max/K i ratio was higher than 0.0025.

Conclusion

A combined pharmacophore and in vitro approach found new, structurally diverse inhibitors for hOCTN2 that may possibly cause clinical significant toxicity such as rhabdomyolysis.

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Abbreviations

MDCK:

Madin–Darby canine kidney

OCTN2:

organic cation/carnitine transporter

QSAR:

quantitative structure activity relationship

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Acknowledgments

This work was supported in part by National Institutes of Health grant DK67530. The authors kindly acknowledge Dr. Xin Ming and Dr. Dhiren R. Thakker (University of North Carolina-Chapel Hill) for providing the hOCTN2-MDCK cell line used in this study. The authors gratefully acknowledge Dr. Matthew D. Krasowski for his assistance in creating the SCUT 2008 database supplemented with metabolites and drugs of abuse. The authors also thank Accelrys, San Diego, CA for making Discovery Studio Catalyst available.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201, USA

    Lei Diao, Sean Ekins & James E. Polli

  2. Collaborations in Chemistry, Jenkintown, Pennsylvania, 19046, USA

    Sean Ekins

  3. Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, 08854, USA

    Sean Ekins

Authors
  1. Lei Diao
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  2. Sean Ekins
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  3. James E. Polli
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Correspondence to James E. Polli.

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Diao, L., Ekins, S. & Polli, J.E. Novel Inhibitors of Human Organic Cation/Carnitine Transporter (hOCTN2) via Computational Modeling and In Vitro Testing. Pharm Res 26, 1890–1900 (2009). https://doi.org/10.1007/s11095-009-9905-3

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  • DOI: https://doi.org/10.1007/s11095-009-9905-3

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