Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors
Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors
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联合虚拟筛选和子结构搜索发现新型 FABP4 抑制剂
DOI：
10.1021/acs.jcim.7b00364
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发表时间：
2017-09-01
影响因子：
5.6
通讯作者：
Chen, Kaixian
中科院分区：
文献类型：
--
作者：
Cai, Haiyan;Wang, Ting;Chen, Kaixian
脂肪酸结合蛋白4（FABP4，AFABP）是糖尿病和动脉粥样硬化的一个潜在药物靶点。在本研究中，通过虚拟筛选和子结构搜索相结合的方法发现了一系列新型FABP4抑制剂。17种化合物表现出对FABP4的抑制活性，半数抑制浓度（IC50）<10μM，其中11种化合物对FABP3显示出高选择性。最佳化合物36b的IC50值为1.5μM。分子对接和点突变研究表明，谷氨酰胺95（Gln95）、精氨酸126（Arg126）和酪氨酸128（Tyr128）在这些化合物与FABP4结合中起关键作用。有趣的是，Gln95似乎对FABP4的构象稳定性至关重要。这些化合物的新骨架及其与FABP4结合的相互作用机制应为新型FABP4抑制剂的进一步开发提供重要线索。
Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 < 10 μM, among which 11 compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 μM. Molecular docking and point mutation studies revealed that Gln95, Arg126, and Tyr128 play key roles for these compounds binding with FABP4. Interestingly, Gln95 seems to be essential for conformation stability of FABP4. The new scaffolds of these compounds and their interaction mechanisms binding with FABP4 should provide an important clue for the further development of novel FABP4 inhibitors.