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@ARTICLE{Gabriel:634622,
      author       = {Gabriel, Florian and Windshügel, Björn and Loew,
                      Christian},
      title        = {{S}tructure‐based discovery of thiamine uptake
                      inhibitors},
      journal      = {British journal of pharmacology},
      volume       = {182},
      number       = {22},
      issn         = {0007-1188},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {PUBDB-2025-02536},
      pages        = {5611 - 5626},
      year         = {2025},
      note         = {DFG (grant numbers INST
                      152/772-1j152/774-1j152/775-1j152/776-1j152/777-1 FUGG).},
      abstract     = {Background and PurposeThiamine (vitamin B1) is an essential
                      coenzyme and catalyses various reactions in central
                      metabolic pathways. Since mammals have lost the ability to
                      synthesise thiamine de novo, this micronutrient has to be
                      imported via the high affinity solute carriers SLC19A2 and
                      A3 across the plasma membrane. Perturbations of these
                      transport systems have severe effects on human health.
                      Recent structural work on SLC19A2 and A3 have provided
                      molecular insights into substrate and drug recognition and
                      conformational changes during transport. Based on the
                      analysis of the available SLC19A3 structures, we hypothesise
                      that the binding site is rather promiscuous, allowing
                      different small molecules to interact and potentially
                      inhibit this transporter.Experimental ApproachWe employed a
                      computational approach, by which 538 approved and
                      investigational drugs were docked into an ensemble of
                      SLC19A3 cryo-EM structures, followed by experimental binding
                      studies, transport inhibition assays, and structural
                      validation.Key ResultsEight novel compounds were identified
                      that bind and inhibit SLC19A3. To visualise such a new drug
                      interaction, we determined the cryo-EM structure of SLC19A3
                      bound to domperidone, a dopamine D2 receptor antagonist used
                      for the treatment of nausea and gastrointestinal disorders.
                      Our computational work together with biochemical and
                      cellular transport assays expands the understanding of
                      SLC19A3-drug interactions, highlights the power of virtual
                      screening approaches using structural ensembles, and
                      provides a three-dimensional pharmacophore model for SLC19A3
                      inhibitors.Conclusion and ImplicationsThese findings offer a
                      basis for addressing drug-induced thiamine deficiencies and
                      pre approach can be used to optimise pharmacological
                      strategies involving SLC19A3-interacting compounds in the
                      future.},
      cin          = {CSSB-EMBL-CL},
      ddc          = {610},
      cid          = {I:(DE-H253)CSSB-EMBL-CL-20210806},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1111/bph.70133},
      url          = {https://bib-pubdb1.desy.de/record/634622},
}