Chemical substructures that enrich for biological activity.
Chemical substructures that enrich for biological activity.
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DOI：
10.1093/bioinformatics/btn479
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Roth FP
中科院分区：
文献类型：
--
作者：
Klekota J;Roth FP
动机：许多药物中都含有特定的化学亚结构。这导致了“特权”子结构的说法，这些子结构容易产生生物活性。由于筛选文库建设中的偏见可以解释这种现象，特权的存在一直存在争议。结果：利用不同的表型分析，我们定义了多个化合物文库的生物活性。即使在解释了亚结构在图书馆中的普遍存在之后，许多亚结构仍然与生物活性有关，从而验证了特权亚结构的概念。特权的确定在独立的分析和文库中得到证实。我们的分析还揭示了“弱势”的子结构和“条件特权”--将子结构的组合与生物活性联系起来的规则。以前报道的大多数亚结构都是平坦的芳香环体系。虽然我们验证了这种子结构，但我们也识别了三维特权子结构。大多数特权亚结构显示了各种各样的取代基，这表明特权的熵机制。含有特权亚结构的化合物的生物活性增加了一倍，这表明了药物发现的实际后果。联系方式：Fritz_Roth@hms.forard.edu补充信息：补充数据可从BioInformation Online获得。
Motivation: Certain chemical substructures are present in many drugs. This has led to the claim of ‘privileged’ substructures which are predisposed to bioactivity. Because bias in screening library construction could explain this phenomenon, the existence of privilege has been controversial. Results: Using diverse phenotypic assays, we defined bioactivity for multiple compound libraries. Many substructures were associated with bioactivity even after accounting for substructure prevalence in the library, thus validating the privileged substructure concept. Determinations of privilege were confirmed in independent assays and libraries. Our analysis also revealed ‘underprivileged’ substructures and ‘conditional privilege’—rules relating combinations of substructure to bioactivity. Most previously reported substructures have been flat aromatic ring systems. Although we validated such substructures, we also identified three-dimensional privileged substructures. Most privileged substructures display a wide variety of substituents suggesting an entropic mechanism of privilege. Compounds containing privileged substructures had a doubled rate of bioactivity, suggesting practical consequences for pharmaceutical discovery. Contact: fritz_roth@hms.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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影响因子：
7.3
作者：
Hajduk, PJ;Bures, M;Fesik, SW
通讯作者：
Fesik, SW
影响因子：
50.3
作者：
Fantin, VR;Berardi, MJ;Leder, P
通讯作者：
Leder, P
DOI：
10.1073/pnas.0631766100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Feng, Y;Yu, S;Kirchhausen, T
通讯作者：
Kirchhausen, T
影响因子：
2.7
作者：
Heinelt, U;Herok, S;Wildgoose, P
通讯作者：
Wildgoose, P
影响因子：
2.7
作者：
Dinnell, K;Chicchi, GG;Swain, CJ
通讯作者：
Swain, CJ