Systematic exploitation of multiple receptor conformations for virtual ligand screening.
Systematic exploitation of multiple receptor conformations for virtual ligand screening.
复制标题
DOI：
10.1371/journal.pone.0018845
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Cavalli A
中科院分区：
文献类型：
--
作者：
Bottegoni G;Rocchia W;Rueda M;Abagyan R;Cavalli A
虚拟配体筛选在现代药物发现中的作用是挖掘大型化学集合，并优先进行实验测试，以针对目标具有预期活性的相对较小和多样化的化合物集进行测试。一些研究指出，考虑到受体的灵活性，可以提高虚拟配体筛选的性能。在这里，我们系统地评估了多种结晶学受体构象，一种离散表示蛋白质可塑性的强大方式，如何在筛选协议中被用于分离结合蛋白和非结合蛋白。我们的分析包括36个与药物相关的目标，并基于报告的针对这些目标的活性的实际分子。结果表明，与标准的单一刚性受体对应物相比，基于集合受体的方案显示出更强的区分活性和非活性分子的能力。此外，这样的方案不仅可以设计成丰富更多的活性化合物，而且还可以增强它们的化学多样性。最后，可以收集一些明确的迹象，说明如何选择在现实生活中最有可能提供最佳性能的受体构象的子集。
The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.
登录
查看更多内容
影响因子：
5.6
作者：
Craig, Ian R.;Essex, Jonathan W.;Spiegel, Katrin
通讯作者：
Spiegel, Katrin
影响因子：
5.6
作者：
Corbeil, Christopher R.;Englebienne, Pablo;Moitessier, Nicolas
通讯作者：
Moitessier, Nicolas
影响因子：
3.5
作者：
Bottegoni, Giovanni;Kufareva, Irina;Abagyan, Ruben
通讯作者：
Abagyan, Ruben
DOI：
10.1002/prot.340190206
发表时间：
1994-06-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
ABAGYAN, R;FRISHMAN, D;ARGOS, P
通讯作者：
ARGOS, P
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M