CROSS-VALIDATED R(2)-GUIDED REGION SELECTION FOR COMPARATIVE MOLECULAR-FIELD ANALYSIS - A SIMPLE METHOD TO ACHIEVE CONSISTENT RESULTS
CROSS-VALIDATED R(2)-GUIDED REGION SELECTION FOR COMPARATIVE MOLECULAR-FIELD ANALYSIS - A SIMPLE METHOD TO ACHIEVE CONSISTENT RESULTS
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DOI：
10.1021/jm00007a003
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发表时间：
1995-03-31
影响因子：
7.3
通讯作者：
TROPSHA, A
中科院分区：
文献类型：
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作者：
CHO, SJ;TROPSHA, A
比较分子场分析（Comparative Molecular Field Analysis，CoMFA）是现代定量构效关系研究的重要工具之一。CoMFA的可预测性通常由交叉验证的相关系数R（2）（q（2））表征。我们对4个数据集（包括7个三尖杉碱酯、20个5-HT 1A受体配体、59个HIV蛋白酶抑制剂和21个类固醇）的CoMFA研究表明，q（2）值对计算机终端上叠加分子的总体取向敏感，当取向通过系统旋转而变化时，q（2）值可以变化多达0.5q（2）单位。为了优化CoMFA，我们开发了一种新的常规交叉验证的R（2）引导区域选择（q（2）-GRS）。我们首先将最初用常规CoMFA获得的矩形晶格细分为125个小盒子，并使用放置在每个盒子内的探针原子以1.0埃的步长进行125次独立分析。然后，我们只选择那些q（2）高于指定的最佳截止值的小盒子。最后，我们用上一步选择的小盒子的并集重复CoMFA。使用上述四个数据集来验证这个新的q（2）-GRS程序。在每种情况下，我们都获得了与取向无关的高q（2），超过了常规CoMFA获得的q。该方法应在未来的CoMFA研究中常规使用，以保证报告的q（2）值的重现性。
Comparative Molecular Field Analysis (CoMFA) is one of the most powerful modern tools for quantitative structure-activity relationship studies. The CoMFA predictability is conventionally characterized by a cross-validated correlation coefficient R(2) (q(2)). Our CoMFA investigation of 4 datasets, including 7 cephalotaxine esters, 20 5-HT1A receptor ligands, 59 inhibitors of HIV protease, and 21 steroids reveals that the q(2) value is sensitive to the overall orientation of superimposed molecules on a computer terminal and can vary by as much as 0.5q(2) units when the orientation is varied by systematic rotation. To optimize CoMFA, we have developed a new routine, cross-validated R(2)-guided region selection (q(2)-GRS). We first subdivide the rectangular lattice obtained initially with conventional CoMFA into 125 small boxes and perform 125 independent analyses using probe atoms placed within each box with the step size of 1.0 Angstrom. We then select only those small boxes for which a q(2) is higher than a specified optimal cutoff value. Finally, we repeat CoMFA with the union of small boxes selected at the previous step. Four datasets described above were used to validate this new q(2)-GRS routine. In each case we have obtained an orientation-independent, high q(2), exceeding the one obtained with the conventional CoMFA. This method shall be used routinely in the future CoMFA studies to guarantee the reproducibility of the reported q(2) values.