3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid MMP-3 Inhibitors: Exploring Automated Docking as Alignment Method

I. Muegge, B. Podlogar
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引用次数: 17

Abstract

A series of CoMFA models have been derived from docking-based and atom-based alignments. The statistics of these approaches has been compared to determine whether a docking approach can be employed as an automated alignment tool for the development of 3D-QSAR models. Using a well-characterized training set of 51 biphenyl carboxylic acid MMP-3 inhibitors, the docking-based alignment provided by a DOCK4/PMF-scoring protocol has yielded statistically significant, cross-validated CoMFA models comparable to those derived with a traditional atom-based alignment technique. Field fit minimization has been applied to refine the atom-based and docking-based alignments. The refinement appears to be beneficial for the docking-based approach. For the atom-based alignment, however, field-fit refinement has not resulted in improved CoMFA models. The statistically best CoMFA model has been created by the atom-based alignment that has been found, however, to be inconsistent with the stromelysin crystal structure. The docking alignment refined by field-fit alignment has resulted in a final alignment that is consistent with the crystal structure and only slightly statistically inferior to the atom-based aligned CoMFA model. The results show␣the ability of an automated docking/field-fit alignment technique to provide self-consistent CoMFA alignments.
联苯羧酸类MMP-3抑制剂的三维定量构效关系:探索自动对接定位方法
一系列的CoMFA模型已经从基于对接和基于原子的对准中衍生出来。对这些方法的统计数据进行了比较,以确定对接方法是否可以作为3D-QSAR模型开发的自动对准工具。使用具有良好特征的51个联苯羧酸MMP-3抑制剂的训练集,由DOCK4/ pmf评分协议提供的基于对接的比对得到了具有统计学意义的交叉验证CoMFA模型,可与传统的基于原子的比对技术相媲美。场拟合最小化已被应用于改进基于原子和基于对接的对准。这种改进似乎对基于对接的方法是有益的。然而,对于基于原子的对准,场拟合的细化并没有导致改进的CoMFA模型。统计上最好的CoMFA模型是由基于原子的排列创建的,然而,它与stromelysin晶体结构不一致。通过场拟合校准改进的对接校准导致最终的校准与晶体结构一致,在统计上仅略低于基于原子的校准CoMFA模型。结果显示,自动化对接/现场拟合对齐技术能够提供自一致的CoMFA对齐。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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