TMEM175 is a lysosomal ion channel that is genetically linked to Parkinson's disease and an emerging therapeutic target for restoring lysosomal homeostasis. Recent cryo-EM structures revealed an agonist binding site occupied by TUG-891 that was previously uncharacterised. However, TUG-891 is a strong FFAR4 agonist, which limits its use as a selective TMEM175 modulator. I propose to use experimentally resolved TMEM175-TUG-891 and FFAR4-TUG-891 complexes to identify structural features that control selectivity. Using SeeSAR and infiniSee, I will use scaffold replacement and pharmacophore-based searches to explore alternative chemical structures that preserve TMEM175 binding and screen against FFAR4 to minimise off-target interactions. This will allow me to find distinct ligands compatible with the agonist-bound TMEM175 conformation while minimising off-target recognition.
Sofia intends to achieve the following milestones:
- Validate the TMEM175–TUG-891 and FFAR4–TUG-891 binding models and identify the key structural differences that could be used.
- Explore scaffolds and chemical space, screen candidates against TMEM175 and FFAR4 to create a diverse shortlist.
- Choose the best candidates with binding mode, ADME and physicochemical properties, and produce a final list for experimental testing