Pharmacophores incorporating numerous excluded volumes defined by X-ray crystallographic structure in three-dimensional database searching: Application to the thyroid hormone receptor
Pharmacophores incorporating numerous excluded volumes defined by X-ray crystallographic structure in three-dimensional database searching: Application to the thyroid hormone receptor
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DOI：
10.1021/jm9708691
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发表时间：
1998-07-02
影响因子：
7.3
通讯作者：
Gillner, M
中科院分区：
文献类型：
--
作者：
Greenidge, PA;Carlsson, B;Gillner, M
在本研究中，我们调查是否扩增的药效团与排除（配体无法访问）的卷可以浓缩的SD数据库搜索中经常获得的冗长的非特异性命中列表。我们的药效团包含由配体大鼠THR-α X射线结构的激素、氢键供体和受体特征定义的疏水性特征，并排除了位于位置处的体积，并根据描绘结合腔的原子大小进行缩放。我们现在第一次证明，使用Catalyst软件在1-2小时内搜索中等规模的数据库，如Maybridge（5 × 10（5）化合物注册为多种构象异构体），其中药效团包含大量（类似于10（2））排除体积，是完全可行的。排除的体积并没有显着减慢搜索;对于含有更多特征的药效团，它们也最大程度地减少了命中列表的大小。例如，使用7个特征药效团，Maybridge命中列表从4个缩减到1个。随后显示出单一剩余化合物以69 μ M的IC 50与THR-α结合。因此，我们得出结论，基于结构的药效团增强与众多的排除量可以有效地修剪和集中试剂盒列表。与其他已发表的程序相比，在速度、特异性和易用性方面，使用Catalyst软件实现的3D数据库挖掘中的多个排除体积补充的基于结构的药效团的性能非常有利。
In the present study we investigate whether augmentation of pharmacophores with excluded (ligand-inaccessible) volumes can condense the lengthy unspecific hit lists often obtained in SD-database searching. Our pharmacophores contained hydrophobic features defined by the hormone, hydrogen bond donor and acceptor features of the liganded rat THR-alpha X-ray structure, and excluded volumes located at the positions and scaled according to the sizes of atoms delineating the binding cavity. We now show, for the first time, that it is perfectly feasible with the Catalyst software to search, in 1-2 h, medium-sized databases such as Maybridge (with 5 x 10(5) compounds registered as multiple conformers) with pharmacophores containing numerous (similar to 10(2)) excluded volumes. The excluded volumes did not slow the search significantly; for pharmacophores containing more f'eatures they also reduced the size of the hit list the most. For example, with a 7-feature pharmacophore, the Maybridge hit list shrank from 4 to 1. The single remaining compound was subsequently shown to bind to THR-alpha with an IC50 of 69 mu M. Thus, we conclude that structure-based pharmacophores augmented with numerous excluded volumes can effectively prune and focus kit lists. The performance of multiple excluded volume-supplemented structure-based pharmacophores in 3D-database mining as implemented with the Catalyst software compares very favorably with other published procedures, with respect to speed, specificity, and ease of use.