A computational approach yields selective inhibitors of human excitatory amino acid transporter 2 (EAAT2). 2020

Kelly L Damm-Ganamet, and Marie-Laure Rives, and Alan D Wickenden, and Heather M McAllister, and Taraneh Mirzadegan
Discovery Sciences, Janssen Research and Development, San Diego, California 92121. Electronic address: kganamet@its.jnj.com.

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.

UI MeSH Term Description Entries
D009435 Synaptic Transmission The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES. Neural Transmission,Neurotransmission,Transmission, Neural,Transmission, Synaptic
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002493 Central Nervous System Diseases Diseases of any component of the brain (including the cerebral hemispheres, diencephalon, brain stem, and cerebellum) or the spinal cord. CNS Disease,Central Nervous System Disease,Central Nervous System Disorder,CNS Diseases,Central Nervous System Disorders
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D014584 User-Computer Interface The portion of an interactive computer program that issues messages to and receives commands from a user. Interface, User Computer,Virtual Systems,User Computer Interface,Interface, User-Computer,Interfaces, User Computer,Interfaces, User-Computer,System, Virtual,Systems, Virtual,User Computer Interfaces,User-Computer Interfaces,Virtual System
D019295 Computational Biology A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories for solving biological problems including manipulation of models and datasets. Bioinformatics,Molecular Biology, Computational,Bio-Informatics,Biology, Computational,Computational Molecular Biology,Bio Informatics,Bio-Informatic,Bioinformatic,Biologies, Computational Molecular,Biology, Computational Molecular,Computational Molecular Biologies,Molecular Biologies, Computational
D027322 Amino Acid Transport System X-AG A family of POTASSIUM and SODIUM-dependent acidic amino acid transporters that demonstrate a high affinity for GLUTAMIC ACID and ASPARTIC ACID. Several variants of this system are found in neuronal tissue. Glutamate-Aspartate Transporter,Amino Acid Transport System XAG,GLAST Glutamate-Aspartate Transporters,Glutamate Translocase,Glutamate Transport Glycoprotein,Glutamate Transporter,Amino Acid Transport System X AG,GLAST Glutamate Aspartate Transporters,Glutamate Aspartate Transporter,Glutamate-Aspartate Transporters, GLAST,Transport Glycoprotein, Glutamate,Transporter, Glutamate-Aspartate,Transporters, GLAST Glutamate-Aspartate

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