Structural diversity of biologically interesting datasets: a scaffold analysis approach.
Structural diversity of biologically interesting datasets: a scaffold analysis approach.
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DOI：
10.1186/1758-2946-3-30
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发表时间：
2011-08-08
影响因子：
8.6
通讯作者：
Ranganathan S
中科院分区：
文献类型：
--
作者：
Khanna V;Ranganathan S
人类代谢组和天然产物数据集的最近公开可用性使“代谢物相似性”和“天然产物相似性”作为设计靶向特定途径的先导文库的药物设计概念重新焕发活力。许多报告已经分析了生物学重要数据集的物理化学性质空间，只有少数全面表征了生物学感兴趣的公共数据集的支架多样性。利用目前大量的高质量公共数据，我们对当前的线索与其他生物学相关数据集进行了比较分析。在这项研究中，我们注意到，与目前使用的铅库（23%）相比，药物数据集中的代谢物支架（42%）富集了两倍。我们还注意到，只有一小部分（5%）的天然产物支架空间被主要数据集共享。我们已经确定了存在于代谢物和天然产物中的特定支架，与药物中的密切对应物，但在主要数据集中缺失。为了确定化合物在物理化学性质空间中的分布，我们分析了分子的极性表面积，分子的溶解度，环的数量和旋转键的数量，除了四个众所周知的Lipinski性质。在这里，我们注意到，除了少数例外，大多数药物都遵循Lipinski规则。代谢产物中分子极性表面积和分子溶解度的平均值最高，而环数最低。此外，我们注意到，天然产物包含最大数量的环和可旋转的债券比任何其他数据集正在考虑。目前使用的铅库很少利用代谢产物和天然产物支架空间。我们认为，代谢产物和天然产物被生物圈中至少一种蛋白质识别，因此，对这些化合物的片段和支架空间进行采样，沿着物理化学性质空间中的分布知识，可以产生更好的先导文库。因此，我们建议在设计铅库时更多地使用代谢物和天然产物。然而，代谢物在化学空间中具有有限的分布，这限制了代谢物在文库设计中的使用。
The recent public availability of the human metabolome and natural product datasets has revitalized "metabolite-likeness" and "natural product-likeness" as a drug design concept to design lead libraries targeting specific pathways. Many reports have analyzed the physicochemical property space of biologically important datasets, with only a few comprehensively characterizing the scaffold diversity in public datasets of biological interest. With large collections of high quality public data currently available, we carried out a comparative analysis of current day leads with other biologically relevant datasets. In this study, we note a two-fold enrichment of metabolite scaffolds in drug dataset (42%) as compared to currently used lead libraries (23%). We also note that only a small percentage (5%) of natural product scaffolds space is shared by the lead dataset. We have identified specific scaffolds that are present in metabolites and natural products, with close counterparts in the drugs, but are missing in the lead dataset. To determine the distribution of compounds in physicochemical property space we analyzed the molecular polar surface area, the molecular solubility, the number of rings and the number of rotatable bonds in addition to four well-known Lipinski properties. Here, we note that, with only few exceptions, most of the drugs follow Lipinski's rule. The average values of the molecular polar surface area and the molecular solubility in metabolites is the highest while the number of rings is the lowest. In addition, we note that natural products contain the maximum number of rings and the rotatable bonds than any other dataset under consideration. Currently used lead libraries make little use of the metabolites and natural products scaffold space. We believe that metabolites and natural products are recognized by at least one protein in the biosphere therefore, sampling the fragment and scaffold space of these compounds, along with the knowledge of distribution in physicochemical property space, can result in better lead libraries. Hence, we recommend the greater use of metabolites and natural products while designing lead libraries. Nevertheless, metabolites have a limited distribution in chemical space that limits the usage of metabolites in library design.
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影响因子：
5.6
作者：
Singh N;Guha R;Giulianotti MA;Pinilla C;Houghten RA;Medina-Franco JL
通讯作者：
Medina-Franco JL
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
3
作者：
Schellenberger J;Park JO;Conrad TM;Palsson BØ
通讯作者：
Palsson BØ
影响因子：
14.9
作者：
Schmidt U;Struck S;Gruening B;Hossbach J;Jaeger IS;Parol R;Lindequist U;Teuscher E;Preissner R
通讯作者：
Preissner R
影响因子：
14.8
作者：
Hert, Jerome;Irwin, John J.;Laggner, Christian;Keiser, Michael J.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.