Ligand Discovery for the Alanine-Serine-Cysteine Transporter (ASCT2, SLC1A5) from Homology Modeling and Virtual Screening
Fig 7
Identification of a potent ASCT2 inhibitor based on the outward-open model.
(A) Predicted binding mode of the new identified inhibitor γ-FBP. The ASCT2 binding site is visualized as gray cartoon; sidechain atoms of key residues are illustrated with gray lines and the ligand is displayed as yellow sticks, with oxygen, nitrogen, and hydrogen atoms in red, blue, and white, respectively; hydrogen bonds between the inhibitor and ASCT2 (involving residues Ser351, Asp464, Thr468 and Asn471) are displayed as dotted black lines. (B) Representative current recordings in response to application of alanine, γ-FBP, and alanine + γ-FBP at conditions indicated in the legend. The gray bar depicts the duration of compound application. (C) Dose response relationship of γ-FBP-induced currents with the number of experiments averaged for each data point illustrated in brackets. (D) Alanine-induced currents (100 μM) in the presence of varying concentrations of γ-FBP (membrane potential = 0 mV, internal buffer contained 130 mM NaSCN and 10 mM alanine, external buffer contained 140 mM NaCl). The number of experiments averaged for each data point is illustrated in brackets. The dashed line represents the relationship based on a Ki of 87 μM, for comparison with (C).