CROSS-VALIDATED R(2)-GUIDED REGION SELECTION FOR COMPARATIVE MOLECULAR-FIELD ANALYSIS - A SIMPLE METHOD TO ACHIEVE CONSISTENT RESULTS

被引：273

作者：

CHO, SJ ^{[1
]}

TROPSHA, A ^{[1
]}

机构：

[1] UNIV N CAROLINA,SCH PHARM,DIV MED CHEM & NAT PROD,MOLEC MODELING LAB,CHAPEL HILL,NC 27599

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 07期

关键词：

D O I：

10.1021/jm00007a003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1060 / 1066

页数：7

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