Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, Japan.
J Pharmacol Sci. 2020 Aug;143(4):264-271. doi: 10.1016/j.jphs.2020.05.005. Epub 2020 May 23.
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.
脂肪酸结合蛋白（FABP）属于蛋白家族，在细胞质中运输脂肪酸，并调节细胞功能，如膜磷脂合成、脂质代谢和线粒体β氧化。在这项研究中，我们从 BMS309403 合成了十个新的衍生物，BMS309403 是一种特定于 FABP4 的联苯唑化合物，并分析了它们对 FABP3、FABP4 和 FABP5 的亲和力和特异性，这三种蛋白在氨基酸序列上有 60%的同源性。在这里，我们使用 1-苯胺基萘-8-磺酸（ANS）置换实验发现，配体 1 对 FABP3 的亲和力最高，对 FABP4 和 FABP5 的亲和力相当。BMS309403 的表观解离常数与花生四烯酸和二十二碳六烯酸相同。与 X 射线结构数据的对接研究表明，这些通过取代 BMS309403 中苯氧基乙酸获得的新型衍生物而不是 BMS309403 对 FABP3 具有高或中等亲和力。我们进一步发现，苯基和烷基取代会导致 16F、门户环和 115L、117L 之间的空间位阻，从而降低它们对 FABPs 的亲和力。总之，我们的研究为开发每种 FABP 的特异性配体提供了一种新策略。
