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.
Ivan R Torrecillas  1 ,  Susana Conde-Ceide  2 ,  Ana Isabel de Lucas  2 ,  Aránzazu Garcı A Molina  2 ,  Andrés A Trabanco  2 ,  Hilde Lavreysen ,  Leonardo Pardo  1 ,  Gary Tresadern
Affiliations
  • 1. Laboratori de Medicina Computacional Unitat de Bioestadistica, Facultat de Medicina , Universitat Autonoma de Barcelona , 08193 , Bellaterra , Spain.
  • 2. Medicinal Chemistry , Janssen Research & Development , Calle Jarama 75A , Toledo 45007 , Spain.
PMID: 30821959 DOI: 10.1021/acschemneuro.9b00019
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.
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