ArticleFrontiers in chemistry2018
Homology Modeling Informs Ligand Discovery for the Glutamine Transporter ASCT2.
Article in Frontiers in chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.Future medicinal chemistry · 2025Review
- Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches.Pharmaceutics · 2024Review
- A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.Cancers · 2023Article
- A Guide to In Silico Drug Design.Pharmaceutics · 2022Review
- Alanine serine cysteine transporter (ASCT) substrate binding site properties probed with hydroxyhomoserine esters.Journal of physical organic chemistry · 2022Article
- Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport.Investigational new drugs · 2022Article
- Mutation in Transmembrane Domain 8 of Human Urate Transporter 1 Disrupts Uric Acid Recognition and Transport.ACS omega · 2022Article
- Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters.Frontiers in pharmacology · 2021Review
- Structural Insights into the Atomistic Mechanisms of Uric Acid Recognition and Translocation of Human Urate Anion Transporter 1.ACS omega · 2020Article
- Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How.International journal of molecular sciences · 2020Review
- Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer.Neurochemical research · 2020Review
- Interaction of the neutral amino acid transporter ASCT2 with basic amino acids.The Biochemical journal · 2020Article
- Amino acid transporters: Emerging roles in drug delivery for tumor-targeting therapy.Asian journal of pharmaceutical sciences · 2020Review
- Glutamine transporters as pharmacological targets: From function to drug design.Asian journal of pharmaceutical sciences · 2020Review
- Advances and Challenges in Rational Drug Design for SLCs.Trends in pharmacological sciences · 2019Review
- Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.The Journal of general physiology · 2019Article
- Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods.International journal of molecular sciences · 2018Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
The Alanine-Serine-Cysteine transporter (SLC1A5, ASCT2), is a neutral amino acid exchanger involved in the intracellular homeostasis of amino acids in peripheral tissues. Given its role in supplying glutamine to rapidly proliferating cancer cells in several tumor types such as triple-negative breast cancer and melanoma, ASCT2 has been identified as a key drug target. Here we use a range of computational methods, including homology modeling and ligand docking, in combination with cell-based assays, to develop hypotheses for structure-function relationships in ASCT2. We perform a phylogenetic analysis of the SLC1 family and its prokaryotic homologs to develop a useful multiple sequence alignment for this protein family. We then generate homology models of ASCT2 in two different conformations, based on the human EAAT1 structures. Using ligand enrichment calculations, the ASCT2 models are then compared to crystal structures of various homologs for their utility in discovering ASCT2 inhibitors. We use virtual screening, cellular uptake and electrophysiology experiments to identify a non-amino acid ASCT2 inhibitor that is predicted to interact with the ASCT2 substrate binding site. Our results provide insights into the structural basis of substrate specificity in the SLC1 family, as well as a framework for the design of future selective and potent ASCT2 inhibitors as cancer therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.