Charting biologically relevant chemical space: A structural classification of natural products (SCONP)
Charting biologically relevant chemical space: A structural classification of natural products (SCONP)
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DOI：
10.1073/pnas.0503647102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
Waldmann, H
中科院分区：
文献类型：
--
作者：
Koch, MA;Schuffenhauer, A;Waldmann, H
在化学生物学和药物化学的研究中，鉴定属于巨大化学空间的生物学相关亚组分的小分子是至关重要的。这些分子满足生物相关性的先决条件是由天然产物衍生的化合物集合满足的。我们报告的天然产物的结构分类（SCNP）的组织原则，绘制已知的化学空间探索的性质。SCNP以树状方式排列天然产物的支架，并为天然产物衍生化合物集合的设计提供可行的分析和假设生成工具。该方法的有效性证明了在一个以前未描述的类的选择性和有效的抑制剂11 β-羟基-类固醇脱氢酶1型与活性的细胞指导下的SCONP和蛋白质结构相似性聚类的发展。1型11 β-羟基类固醇脱氢酶是开发用于治疗糖尿病、代谢综合征和肥胖症的新疗法的靶点。
The identification of small molecules that fall within the biologically relevant subfraction of vast chemical space is of utmost importance to chemical biology and medicinal chemistry research. The prerequirement of biological relevance to be met by such molecules is fulfilled by natural product-derived compound collections. We report a structural classification of natural products (SCONP) as organizing principle for charting the known chemical space explored by nature. SCONP arranges the scaffolds of the natural products in a tree-like fashion and provides a viable analysis- and hypothesis-generating tool for the design of natural product-derived compound collections. The validity of the approach is demonstrated in the development of a previously undescribed class of selective and potent inhibitors of 11 beta-hydroxy-steroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11 beta-hydroxy-steroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.