Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
J Comput Aided Mol Des. 2011 Feb;25(2):107-16. doi: 10.1007/s10822-010-9398-5. Epub 2010 Nov 11.
In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.
在寻找更有效和安全的抗糖尿病化合物的过程中，我们基于 PPARγ 的部分激动剂开发了一个药效团模型。该模型用于虚拟筛选中国天然产物数据库（CNPD），这是一个主要用于民间医学的植物源性天然产物库。从得到的命中结果中，我们选择了甲基油烯酸酯，它是在黄连木树脂（奇亚乳香胶）中发现的一种化合物。甲基油烯酸的酸，即齐墩果酸，通过奇亚乳香胶馏分的生物测定指导的色谱分离被鉴定为 PPARγ 激动剂，而其他一些亚馏分也表现出对 PPARγ 的生物活性。本工作的结果有两方面：一方面，我们证明了我们开发的药效团模型能够选择新型的配体支架，这些支架作为 PPARγ 激动剂起作用；同时，它表明天然产物对于基于虚拟筛选的药物发现非常重要。
