Portal de Periódicos da CAPES

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

2009; Springer Science+Business Media; Volume: 26; Issue: 8 Linguagem: Inglês

10.1007/s11095-009-9905-3

1573-904X

Lei Diao, Sean Ekins, James E. Polli,

Neurological and metabolic disorders

The objective was to elucidate the inhibition requirements of the human organic cation/carnitine transporter (hOCTN2). 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. 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. A combined pharmacophore and in vitro approach found new, structurally diverse inhibitors for hOCTN2 that may possibly cause clinical significant toxicity such as rhabdomyolysis.