Novel approach to structure-based pharmacophore search using computational geometry and shape matching techniques
Novel approach to structure-based pharmacophore search using computational geometry and shape matching techniques
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DOI：
10.1021/ci700368p
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发表时间：
2008-04-01
影响因子：
5.6
通讯作者：
Zheng, Weifan
中科院分区：
文献类型：
--
作者：
Ebalunode, Jerry Osagie;Ouyang, Zheng;Zheng, Weifan
计算效率高的结构为基础的虚拟筛选方法最近已被报道，试图找到有效的手段，利用实验结构信息，而不采用详细的分子对接计算。这些工具可以与有效的实验筛选技术相结合，以提高识别药物发现研究的命中和线索的概率。来自Open Eye Scientific的商业软件ROCS（化学结构的快速叠加）就是这样的例子，其是使用配体的3D结构（通常来自结合的X射线共结构）作为查询的基于形状的虚拟筛选方法。我们在这里报告的发展，一个新的基于结构的药效团搜索方法（称为形状4）的虚拟筛选。这种方法采用了ROCS形状技术的一种变体，并将其应用扩展到与一个。空的晶体结构它采用严格的计算几何方法和确定性几何铸造算法来导出负像（即，假配体）。一旦生成负像（或伪配体），就采用商业OE SHAPE Toolkit中的高效形状比较算法来将小有机分子与伪配体的形状进行比较和匹配。我们使用从WOMBAT数据库中提取的已知生物活性化合物报告了详细的计算方案及其计算验证。五个选定的目标衍生的模型被用来执行虚拟筛选实验，以获得各种虚拟筛选方法的富集数据。结果发现，我们的方法提供了类似或更好的富集比比其他相关的方法，往往具有更好的多样性排名靠前的计算命中。
Computationally efficient structure-based virtual screening methods have recently been reported that seek to find effective means to utilize experimental structure information without employing detailed molecular docking calculations. These tools can be coupled with efficient experimental screening technologies to improve the probability of identifying hits and leads for drug discovery research. Commercial software ROCS (rapid overlay of chemical structures) from Open Eye Scientific is such an example, which is a shape-based virtual screening method using the 3D structure of a ligand, typically from a bound X-ray costructure, as the query. We report here the development of a new structure-based pharmacophore search method (called Shape4) for virtual screening. This method adopts a variant of the ROCS shape technology and expands its use to work with an. empty crystal structure. It employs a rigorous computational geometry method and a deterministic geometric casting algorithm to derive the negative image (i.e., pseudoligand) of a target binding site. Once the negative image (or pseudoligand) is generated, an efficient shape comparison algorithm in the commercial OE SHAPE Toolkit is adopted to compare and match small organic molecules with the shape of the pseudoligand. We report the detailed computational protocol and its computational validation using known biologically active compounds extracted from the WOMBAT database. Models derived for five selected targets were used to perform the virtual screening experiments to obtain the enrichment data for various virtual screening methods. It was found that our approach afforded similar or better enrichment ratios than other related methods, often with better diversity among the top ranking computational hits.