Lessons for fragment library design: analysis of output from multiple screening campaigns
Lessons for fragment library design: analysis of output from multiple screening campaigns
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DOI：
10.1007/s10822-009-9280-5
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Hubbard, Roderick E.
中科院分区：
文献类型：
--
作者：
Chen, I-Jen;Hubbard, Roderick E.
在过去的 8 年里，我们开发、完善并应用了基于片段的发现方法来研究一系列蛋白质靶点。在这里，我们报告了片段库各个方面的计算分析以及片段筛选获得的结果。我们强化了其他人的发现，即实验观察到的筛选片段的命中率可能与计算定义的靶标成药性指数相关。一般来说，片段命中的物理化学特性显示出与文库相同的特征，正如对于探测相关化学空间的真正多样化的文库所期望的那样。对各种蛋白质类别的片段命中分析表明，片段的理化特性与靶结合位点的特性互补。一些片段的有效性似乎是通过药效团特征和增强芳香性的适当组合来实现的，其中疏水相互作用发挥着重要作用。该分析强调，可以识别不同结合位点特异的小片段。最后，我们讨论了结果如何为我们的片段库的进一步开发和改进提供信息。
Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library.