Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation.
Pharmacol Res
; 196: 106941, 2023 Oct.
Article
em En
| MEDLINE
| ID: mdl-37775020
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.
Palavras-chave
5-Methylcytidine (PubChem CID: 92918); Anserine (PubChem CID: 112072); Capecitabine (PubChem CID: 60953); Cytarabine (PubChem CID: 6253); Cytosine (PubChem CID: 597); Drug screening; Drug transport; Flucytosine (PubChem CID: 3366); Gemcitabine (PubChem CID: 60750); In silico screening; Metabolomics; Multidrug and toxin extrusion protein 1; Proton-coupled peptide transporter 2
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana Transportadoras
/
Proteínas Carreadoras de Solutos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article