Structure-based discovery of thiamine uptake inhibitors

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Thiamine (vitamin B1) is vital for metabolic pathways, requiring import via SLC19A2 and SLC19A3 transporters.
• Disruptions in thiamine transport significantly impact human health.
• Recent structural studies revealed insights into SLC19A2 and SLC19A3 substrate binding and transport mechanisms.

Purpose of the Study:

• To investigate the promiscuity of the SLC19A3 binding site for potential inhibitors.
• To identify novel compounds that interact with and inhibit the SLC19A3 transporter.
• To expand the understanding of SLC19A3-drug interactions.

Main Methods:

• Computational drug docking of 538 drugs into SLC19A3 cryo-EM structures.
• Experimental binding studies and transport inhibition assays.
• Cryo-EM structure determination of SLC19A3 bound to domperidone.

Main Results:

• Eight novel compounds were identified that bind to and inhibit SLC19A3.
• The cryo-EM structure of SLC19A3 complexed with domperidone was determined.
• Computational and experimental data provide a 3D pharmacophore model for SLC19A3 inhibitors.

Conclusions:

• The findings provide a foundation for addressing drug-induced thiamine deficiencies.
• Virtual screening using structural ensembles is a powerful approach for drug discovery.
• This research can optimize future pharmacological strategies targeting SLC19A3.