设计针对果糖 1,6-二磷酸酶的抑制剂：探索天然产物以寻找新型抑制剂支架。
Designing inhibitors against fructose 1,6-bisphosphatase: exploring natural products for novel inhibitor scaffolds.
机构信息
Department of Chemistry, Boston College, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA.
出版信息
Eur J Med Chem. 2010 Apr;45(4):1478-84. doi: 10.1016/j.ejmech.2009.12.055. Epub 2010 Jan 13.
Abstract
Natural products often contain unusual scaffold structures that may be elaborated by combinatorial methods to develop new drug-like molecules. Visual inspection of more than 128 natural products with some type of anti-diabetic activity suggested that a subset might provide novel scaffolds for designing potent inhibitors against fructose 1,6-bisphosphatase (FBPase), an enzyme critical in the control of gluconeogenesis. Using in silico docking methodology, these were evaluated to determine those that exhibited affinity for the AMP binding site. Achyrofuran from the South American plant Achyrocline satureoides, was selected for further investigation. Using the achyrofuran scaffold, inhibitors against FBPase were developed. Compounds 15 and 16 inhibited human liver and pig kidney FBPases at IC50 values comparable to that of AMP, the natural allosteric inhibitor.
摘要
天然产物通常含有不寻常的骨架结构，可以通过组合方法进行修饰，从而开发出新的类似药物的分子。对具有某种类型抗糖尿病活性的 128 多种天然产物进行目视检查后表明，其中一部分可能为设计针对果糖 1,6-二磷酸酶 (FBPase) 的有效抑制剂提供新的骨架，FBPase 是控制糖异生的关键酶。使用计算机对接方法对这些天然产物进行评估，以确定那些与 AMP 结合位点具有亲和力的天然产物。来自南美洲植物 Achyrocline satureoides 的 Achyrofuran 被选中进行进一步研究。利用 Achyrofuran 骨架，开发出了针对 FBPase 的抑制剂。化合物 15 和 16 以与 AMP（天然变构抑制剂）相当的 IC50 值抑制人肝和猪肾 FBPases。
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