Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia; Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD 4229, Australia.
Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia; School of Biomolecular and Physical Sciences, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia.
Eur J Med Chem. 2014 Sep 12;84:584-94. doi: 10.1016/j.ejmech.2014.07.063. Epub 2014 Jul 19.
A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.
合成了一系列吗啉取代的氨基酸（苯丙氨酸、亮氨酸、赖氨酸和谷氨酸）。然后采用基于片段的筛选方法来评估一系列小杂环化合物，包括吗啉、恶唑啉、二氢-1,3-恶嗪、四氢-1,3-恶嗪、噻唑啉、四氢-1,3-嘧啶、四氢-1,3-二氮杂环庚烷和六氢-1H-苯并咪唑，作为糖原磷酸化酶 a 的潜在抑制剂。与杂环化合物 1、5、9-13 和 19（IC50 值为 1.1 mM-23.9 mM）相比，噻唑啉 7 表现出改善的效力（IC50 为 25 μM），并且具有良好的 LE 和 LELP 值。使用人肝糖原磷酸化酶的晶体结构进行的对接研究提供了杂环化合物 5、7、9-13 和 19 与糖原磷酸化酶相互作用的深入了解。
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