[Background] We previously revealed α-synuclein aggregation is promoted by fatty acid-binding protein 3 (FABP3). Development of their ligands has been performed for FABP4. In this report, we analyzed the affinity and binding property of ligands for FABP3.
[Methods] Recombinant FABPs was purified from E. Coli. We used arachidonic acid (AA), FABP4 ligand (BMS309403) and its ten derivatives in ANS assay and investigated their affinity to FABPs. Also, we analyzed binding properties of PA-FABP4 and BMS-FABP3 complex from their crystal structures using PLIP. We further performed prediction analysis of BMS derivative-FABP3 complex structure with docking simulation and PLIP.
[Results and Discussion] AA showed high affinity to both FABP3 and 4 (Kd = 133 and 674 nM respectively). BMS showed higher affinity to FABP4 (Kd = 593 nM) rather than FABP3 (Kd = 34,920 nM) Among ten derivatives, ligand #1 showed the highest affinity to FABP3 (Kd = 261 nM), however identical to FABP4. PLIP study revealed AA and BMS bind with FABP4 by similar interactions. Prediction analysis indicated 104Ile in FABP3 caused steric obstruction with BMS, which might explain its high selectivity to FABP4. These results will lead to further research for FABP3-selective ligand.