Lead Optimization in the SLC7A11 Membrane Protein System
Molecular dynamics simulation
Background
• The SLC7A11 light chain pairs with the SLC3A2 heavy chain to form system Xc⁻, a functional cystine-glutamate antiporter. SLC3A2 serves as a chaperone protein, stabilizing SLC7A11.
• System Xc⁻ operates within the cell membrane, facilitating cystine uptake and glutamate export.
• The available cryo-EM structure of the SLC7A11 complex is low-resolution, resulting in an unclear depiction of the erastin binding site and complicating accurate docking of the drug’s binding mode.
Approach
Results
• 42 compounds demonstrated significant inhibitory effects on glutamate release and exhibited notable cytotoxic activity.
• Compound 5 showed a 30-fold increase in cystine uptake activity compared to the positive control, and has been shown to promote the healing of diabetic foot ulcers.
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