دورية أكاديمية
A computational approach yields selective inhibitors of human excitatory amino acid transporter 2 (EAAT2).
| العنوان: | A computational approach yields selective inhibitors of human excitatory amino acid transporter 2 (EAAT2). |
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| المؤلفون: | Damm-Ganamet KL; Discovery Sciences, Janssen Research and Development, San Diego, California 92121. Electronic address: kganamet@its.jnj.com., Rives ML; Discovery Sciences, Janssen Research and Development, San Diego, California 92121., Wickenden AD; Discovery Sciences, Janssen Research and Development, San Diego, California 92121., McAllister HM; Discovery Sciences, Janssen Research and Development, San Diego, California 92121., Mirzadegan T; Discovery Sciences, Janssen Research and Development, San Diego, California 92121. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2020 Mar 27; Vol. 295 (13), pp. 4359-4366. Date of Electronic Publication: 2020 Feb 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Amino Acid Transport System X-AG/*antagonists & inhibitors , Binding Sites/*drug effects , Central Nervous System Diseases/*drug therapy , Excitatory Amino Acid Transporter 2/*antagonists & inhibitors, Amino Acid Transport System X-AG/chemistry ; Amino Acid Transport System X-AG/genetics ; Animals ; Binding Sites/genetics ; Biological Transport/drug effects ; Central Nervous System Diseases/genetics ; Central Nervous System Diseases/pathology ; Computational Biology ; Excitatory Amino Acid Transporter 2/chemistry ; Excitatory Amino Acid Transporter 2/genetics ; Humans ; Protein Binding/drug effects ; Synaptic Transmission/drug effects ; User-Computer Interface |
| مستخلص: | 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. Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article. (© 2020 Damm-Ganamet et al.) |
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| فهرسة مساهمة: | Keywords: SLC1A; allosteric regulation; drug discovery; excitatory amino acid transporters; glutamate; glutamate transporter; high throughput virtual screening; homology modeling; neurological disease; neurotransmitter |
| سلسلة جزيئية: | PDB 4P19; 1XFH; 5LLM; 5LLU; 5LM4; 5MJU |
| المشرفين على المادة: | 0 (Amino Acid Transport System X-AG) 0 (Excitatory Amino Acid Transporter 2) 0 (SLC1A2 protein, human) |
| تواريخ الأحداث: | Date Created: 20200222 Date Completed: 20201209 Latest Revision: 20240229 |
| رمز التحديث: | 20240229 |
| مُعرف محوري في PubMed: | PMC7105306 |
| DOI: | 10.1074/jbc.AC119.011190 |
| PMID: | 32079674 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.AC119.011190 |