Topomer CoMFA: A design methodology for rapid lead optimization
Topomer CoMFA: A design methodology for rapid lead optimization
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DOI：
10.1021/jm020194o
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发表时间：
2003-01-30
影响因子：
7.3
通讯作者：
Cramer, RD
中科院分区：
文献类型：
--
作者：
Cramer, RD
为了提供一种可能加速铅优化的客观QSAR方法，CoMFA和Topmer技术被合并，取得了令人惊讶的良好结果。一系列输入结构中的每一个在中心非环单键处被分解成两个或多个片段，同时去除整个系列在结构上共有的任何核心片段。为每个碎片自动构建标准的拓扑体3D模型，并为每组拓扑体生成一组立体和静电场(“CoMFA柱”)。对文献中的15个结构进行三维定量构效关系分析均获得成功，平均Q(2)为0.520(文献平均Q(2)=0.636)，预测的平均标准差为0.688(文献平均为0.553)。Topmer CoMFA的结果特别有希望，因为查询已经由Topmer结构组成的虚拟文库，以直接寻找具有更高效力的结构。因此，在所尝试的15个这种“拓扑体CoMFA搜索”中的13个中，检索到商业提供的片段的组合，这些片段被预测为比原始文献中描述的任何结构更有效(平均预测效价增加=20倍)，原则上显示如何进行最优化。
To provide an objective QSAR methodology that might accelerate lead optimization, the CoMFA and topomer technologies have been merged, with surprisingly good results. A series of input structures are each broken into two or more fragments at central acyclic single bonds, while removing any core fragment structurally common to the entire series. Standard topomer 3D models are automatically constructed for each fragment, and a set of steric and electrostatic fields ("CoMFA column") is generated for each set of topomers. Application of "topomer CoMFA" to 15 3D-QSAR analyses taken from the literature (847 structures) were all successful, with an average q(2) of 0.520 (literature average q(2) = 0.636) and an average standard deviation of true prediction (SDEP) of 0.688 (literature average SDEP = 0.553) for 133 structures. Topomer CoMFA results are particularly promising as queries into virtual libraries already composed of topomer structures, to directly seek structures having increased potency. Accordingly, in 13 of the 15 such "topomer CoMFA searches" attempted, combinations of commercially offered fragments were retrieved that were predicted to be more potent than any structure described in the original publication (average predicted potency increase = 20 x), showing in principle how optimization could occur.