Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation

Nies AT, König J, Leuthold P, Damme K, Winter S, Haag M, Masuda S, Kruck S, Daniel H, Spanier B, Fromm M, Bedke J, Inui Ki, Schwab M, Schaeffeler E (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Pharmacological Research Elsevier

Book Volume: 196

Article Number: 106941

DOI: 10.1016/j.phrs.2023.106941

Abstract

Solute carrier (SLC) transport proteins are fundamental for the translocation of endogenous compounds and drugs across membranes, thus playing a critical role in disease susceptibility and drug response. Because only a limited number of transporter substrates are currently known, the function of a large number of SLC transporters is elusive. Here, we describe the proof-of-concept of a novel strategy to identify SLC transporter substrates exemplarily for the proton-coupled peptide transporter (PEPT) 2 (SLC15A2) and multidrug and toxin extrusion (MATE) 1 transporter (SLC47A1), which are important renal transporters of drug reabsorption and excretion, respectively. By combining metabolomic profiling of mice with genetically-disrupted transporters, in silico ligand screening and in vitro transport studies for experimental validation, we identified nucleobases and nucleoside-derived anticancer and antiviral agents (flucytosine, cytarabine, gemcitabine, capecitabine) as novel drug substrates of the MATE1 transporter. Our data confirms the successful applicability of this new approach for the identification of transporter substrates in general, which may prove particularly relevant in drug research.

Authors with CRIS profile

Jörg König Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Eberhard Karls Universität Tübingen DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Kyoto Pharmaceutical University / 京都薬科大学 JP Japan (JP) Kyushu University / 九州大学 JP Japan (JP)

How to cite

APA:

Nies, A.T., König, J., Leuthold, P., Damme, K., Winter, S., Haag, M.,... Schaeffeler, E. (2023). Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation. Pharmacological Research, 196. https://doi.org/10.1016/j.phrs.2023.106941

MLA:

Nies, Anne T., et al. "Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation." Pharmacological Research 196 (2023).

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