Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering?: An investigation of the advantages and pitfalls of post-filtering
Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering?: An investigation of the advantages and pitfalls of post-filtering
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DOI：
10.1016/j.jmgm.2007.11.005
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发表时间：
2008-06-01
影响因子：
2.9
通讯作者：
Karlen, Anders
中科院分区：
文献类型：
--
作者：
Muthas, Daniel;Sabnis, Yogesh A.;Karlen, Anders
我们已经研究了过滤后的虚拟筛选结果，以及从X射线结构产生的药效学特征对富集率的影响。这是使用三个对接软件zdock+、Surflex和FRED进行的，作为虚拟筛选工具和从共结晶络合物中统一生成的药效团。一组已知的活性物质以及9997个与药物相关的诱骗化合物被对接到六个化学上不同的蛋白质Tat-get，即CDK2，COX2，ERα，FXα，MMP3和NA。为了克服众所周知的对接问题的固有局限性，我们为每个化合物生成了多个姿势。这些化合物首先根据它们的得分进行排名，然后只使用每个化合物得分最高的姿势来计算富集率。随后，每个化合物的所有姿势都通过共结晶络合物产生的不同药物库，并根据每个化合物的得分最高的传递姿势重新计算浓缩因子。与单独对接相比，只使用一个X射线复合体产生的药效基团进行后过滤，可以提高所有被调查目标的富集率。这表明这是一种通用的方法，适用于不同的目标和不同的对接软件。(C)2007 Elsevier Inc.保留所有权利。
We have investigated the influence of post-filtering virtual screening results, with pharmacophorie features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED,as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein tat-gets namely CDK2, COX2, ER alpha, fX alpha, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacoph ores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each Compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares. (C) 2007 Elsevier Inc. All rights reserved.