Analysis of binding affinity and docking of novel fatty acid-binding protein (FABP) ligands

• Published in: Journal of pharmacological sciences Vol. 143; no. 4; pp. 264 - 271
• Main Authors: Shinoda, Yasuharu, Wang, Yifei, Yamamoto, Tetsunori, Miyachi, Hiroyuki, Fukunaga, Kohji
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2020; Elsevier
• Subjects: ANS displacement Assay; BMS309403 derivatives; Fatty acid-binding protein; Ligand docking; Protein-ligand interaction; PUFA; ANS; PLIP; MUFA; ANS displacement Assay; FABP; GST; ARA; Fatty acid-binding protein; Ligand docking; FA; DHA; BMS309403 derivatives; Protein-ligand interaction
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2020.05.005

Fatty acid-binding proteins (FABPs) belong to a family of proteins that transports fatty acids in the cytosol and regulates cellular functions like membrane phospholipid synthesis, lipid metabolism, and mitochondrial β oxidation. In this study, we synthesized ten novel derivatives from BMS309403, a biphenyl azole compound specific for FABP4, and analyzed their affinity and specificity for FABP3, FABP4, and FABP5, which possess 60% of homology in amino acid sequence. Here, we used 1-anilinonaphthalene 8-sulfonic acid (ANS) displacement assay and found that Ligand 1 has highest affinity for FABP3, with comparable affinity for FABP4 and FABP5. The apparent dissociation constant of BMS309403 was identical to that of arachidonic acid and docosahexaenoic acid. Docking studies with X-ray structural data showed that these novel derivatives obtained by the substitution of phenoxyacetic acid in BMS309403 but not BMS309403 have high or moderate affinity for FABP3. We further found that substitution of a phenyl group and alkyl group caused steric hindrance between 16F, the portal loop and 115L, 117L, respectively, leading to decrease in their affinity for FABPs. In conclusion, our study provides a novel strategy for development of specific ligand for each FABP.