Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China; Chemistry and Chemical Engineering, Nantong University, Jiangsu 226019, China.
Eur J Med Chem. 2014 Aug 18;83:15-25. doi: 10.1016/j.ejmech.2014.06.011. Epub 2014 Jun 10.
With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.
为了发现一类新型的非磷果糖-1,6-二磷酸酶（FBPase）抑制剂，我们基于高通量筛选（HTS）得到的命中化合物（1），合成了一系列 2,5-二苯基-1,3,4-恶二唑。结构-活性关系（SAR）研究确定了几种与 AMP（FBPase 的天然别构抑制剂）具有相当抑制活性的化合物。值得注意的是，带有末端羧基或 1H-四唑的化合物 22 和 27b 对糖异生（GNG）具有显著的抑制作用。此外，还通过酶动力学和代表性化合物 16 和 22 的计算机模拟实验研究了它们对酶的抑制和结合模式。
