Inhibition of the Alanine-Serine-Cysteine-1 Transporter by BMS-466442

ACS Chem Neurosci. 2019 May 15;10(5):2510-2517. doi: 10.1021/acschemneuro.9b00019. Epub 2019 Mar 14.

Abstract

Experiment and modeling were combined to understand inhibition of the alanine-serine-cysteine-1 (asc1) transporter. The structure-activity relationship (SAR) was explored with synthesis of analogues of BMS-466442. Direct target interaction and binding site location between TM helices 6 and 10 were confirmed via site directed mutagenesis. Computational modeling suggested the inhibitor binds via competitive occupation of the orthosteric site while also blocking the movement of TM helices that are required for transport.

Keywords: SDM; SLC7A10.; asc1; binding mode; homology model; mutagenesis; transporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / antagonists & inhibitors*
  • Amino Acid Transport System y+ / antagonists & inhibitors*
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Histidine / analogs & derivatives*
  • Histidine / pharmacology
  • Humans
  • Indoles / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Amino Acid Transport System ASC
  • Amino Acid Transport System y+
  • BMS-466442
  • Indoles
  • SLC7A10 protein, human
  • Slc7a10 protein, rat
  • Histidine