PMID- 32079674
OWN - NLM
STAT- MEDLINE
DCOM- 20201209
LR  - 20240229
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 295
IP  - 13
DP  - 2020 Mar 27
TI  - A computational approach yields selective inhibitors of human excitatory amino 
      acid transporter 2 (EAAT2).
PG  - 4359-4366
LID - S0021-9258(17)48760-6 [pii]
LID - 10.1074/jbc.AC119.011190 [doi]
AB  - 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.
CI  - (c) 2020 Damm-Ganamet et al.
FAU - Damm-Ganamet, Kelly L
AU  - Damm-Ganamet KL
AD  - Discovery Sciences, Janssen Research and Development, San Diego, California 
      92121. Electronic address: kganamet@its.jnj.com.
FAU - Rives, Marie-Laure
AU  - Rives ML
AD  - Discovery Sciences, Janssen Research and Development, San Diego, California 
      92121.
FAU - Wickenden, Alan D
AU  - Wickenden AD
AD  - Discovery Sciences, Janssen Research and Development, San Diego, California 
      92121.
FAU - McAllister, Heather M
AU  - McAllister HM
AD  - Discovery Sciences, Janssen Research and Development, San Diego, California 
      92121.
FAU - Mirzadegan, Taraneh
AU  - Mirzadegan T
AD  - Discovery Sciences, Janssen Research and Development, San Diego, California 
      92121.
LA  - eng
SI  - PDB/4P19
SI  - PDB/1XFH
SI  - PDB/5LLM
SI  - PDB/5LLU
SI  - PDB/5LM4
SI  - PDB/5MJU
PT  - Journal Article
DEP - 20200220
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acid Transport System X-AG)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (SLC1A2 protein, human)
SB  - IM
MH  - Amino Acid Transport System X-AG/*antagonists & inhibitors/chemistry/genetics
MH  - Animals
MH  - Binding Sites/*drug effects/genetics
MH  - Biological Transport/drug effects
MH  - Central Nervous System Diseases/*drug therapy/genetics/pathology
MH  - Computational Biology
MH  - Excitatory Amino Acid Transporter 2/*antagonists & inhibitors/chemistry/genetics
MH  - Humans
MH  - Protein Binding/drug effects
MH  - Synaptic Transmission/drug effects
MH  - User-Computer Interface
PMC - PMC7105306
OTO - NOTNLM
OT  - SLC1A
OT  - allosteric regulation
OT  - drug discovery
OT  - excitatory amino acid transporters
OT  - glutamate
OT  - glutamate transporter
OT  - high throughput virtual screening
OT  - homology modeling
OT  - neurological disease
OT  - neurotransmitter
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article.
EDAT- 2020/02/23 06:00
MHDA- 2020/12/15 06:00
PMCR- 2021/03/27
CRDT- 2020/02/22 06:00
PHST- 2019/09/20 00:00 [received]
PHST- 2020/02/17 00:00 [revised]
PHST- 2020/02/23 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/02/22 06:00 [entrez]
PHST- 2021/03/27 00:00 [pmc-release]
AID - S0021-9258(17)48760-6 [pii]
AID - AC119.011190 [pii]
AID - 10.1074/jbc.AC119.011190 [doi]
PST - ppublish
SO  - J Biol Chem. 2020 Mar 27;295(13):4359-4366. doi: 10.1074/jbc.AC119.011190. Epub 
      2020 Feb 20.