A computational approach yields selective inhibitors of human excitatory amino acid transporter 2 (EAAT2).
J Biol Chem
; 295(13): 4359-4366, 2020 03 27.
Article
en En
| MEDLINE
| ID: mdl-32079674
ABSTRACT
Excitatory amino acid transporters (EAATs) represent a protein family that is an emerging drug target with great therapeutic potential for managing central nervous system disorders characterized by dysregulation of glutamatergic neurotransmission. As such, it is of significant interest to discover selective modulators of EAAT2 function. Here, we applied computational methods to identify specific EAAT2 inhibitors. Utilizing a homology model of human EAAT2, we identified a binding pocket at the interface of the transport and trimerization domain. We next conducted a high-throughput virtual screen against this site and identified a selective class of EAAT2 inhibitors that were tested in glutamate uptake and whole-cell electrophysiology assays. These compounds represent potentially useful pharmacological tools suitable for further exploration of the therapeutic potential of EAAT2 and may provide molecular insights into mechanisms of allosteric modulation for glutamate transporters.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sitios de Unión
/
Enfermedades del Sistema Nervioso Central
/
Sistema de Transporte de Aminoácidos X-AG
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Transportador 2 de Aminoácidos Excitadores
Límite:
Animals
/
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article