Authors
Morgan, P., Wang, W.-A., Superti-Furga, G., Schlessinger, A.
Abstract
The Na+-dependent citrate transporter NaCT (SLC13A5) is a key regulator of citrate homeostasis and has emerged as a therapeutic target for metabolic and neurological disease, including the SLC13A5 Epilepsy, a rare disease marked by severe sezures and neurodevelopmental delays. Current NaCT inhibitors are substrate-like molecules that competitively bind the substrate binding site. In this study, we identify previously unknown small molecule inhibitors of NaCT by targeting a putative allosteric site located at the dimer interface. We performed a virtual screen of 3.5 million compounds from the ZINC20 database against this site and selected 54 candidates for experimental testing using a cell-based citrate uptake assay. Through initial experiments, we identified three weak inhibitors, and subsequent evaluation of 26 structurally related analogs yielded six compounds with improved potency (IC = 12.78 M and 15.49 M). We then performed further analysis of the putative binding site by integrating structural data with deep mutational scanning evidence and comparisons with homolog structures. This analysis highlighted the importance of key residues (e.g., Phe362) in ligand modulation. These findings reveal a promising allosteric pocket and establish a chemically distinct series of NaCT inhibitors, providing a foundation for rational development of pharmacological modulators of NaCT function.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Jun 2026.
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