PubChem3D: Conformer generation
PubChem3D: Conformer generation
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DOI：
10.1186/1758-2946-3-4
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发表时间：
2011-01-27
影响因子：
8.6
通讯作者：
Bryant, Stephen H.
中科院分区：
文献类型：
--
作者：
Bolton, Evan E.;Kim, Sunghwan;Bryant, Stephen H.
背景资料：PubChem是一个小分子生物学活动的开放档案，提供搜索和分析工具，以帮助用户查找所需的信息。这些工具中的许多工具在某种程度上侧重于化学结构相似性的概念。PubChem 3D支持化学结构3-D构象的相似性，以增强2-D化学结构图的现有相似性。还希望将化学结构的理论3-D描述与实验生物活性相关联。因此，重要的是要确保理论构象模型可以重现实验确定的生物活性构象。在本研究中，我们研究了三个主要的构象生成参数（片段采样率，能量窗口大小和力场变量）对理论构象模型准确性的影响，并确定了PubChem 3D构象模型生成和构象采样的最佳设置。为25，972个小分子配体生成了理论3-D构象模型，其3-D结构通过实验确定。系统地测试主要构象生成参数的不同值以找到最佳设置。采用比默认值更大的片段采样率并没有提高理论构象异构体模型集合的准确性。不断增加的能量窗口确实提高了整体平均精度，在10 kcal/mol和15 kcal/mol下分别观察到模型构建和扭转搜索的快速收敛;然而，随后的研究表明，扭转搜索的能量阈值为25 kcal/mol，导致更大和更灵活的结构的结果略有改善。排除库仑条款的94 s变体的默克分子力场（MMFF 94 s）在扭转搜索阶段得到更准确的构象模型在较低的能量窗口。生物活性构象的再现的总体平均准确度相对于非氢原子计数（“尺寸”）和有效转子计数（“柔性”）两者是显著线性的。使用这些作为自变量，回归方程被开发来预测的RMSD的准确性的理论合奏再现生物活性构象。该方程进行了修改，以得到一个最小的RMSD构象采样值，以帮助确保90%的采样理论模型应包含至少一个构象内的RMSD采样值的“生物活性”conformation.Conclusion：最佳参数的构象生成使用OMEGA进行了探索和确定。开发了一个方程，该方程提供了一个RMSD采样值，该采样值基于重现生物活性构象的相对准确度。PubChem 3D项目使用确定的最佳构象生成参数和RMSD采样值生成理论构象模型。
Background: PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling.Results: Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation.Conclusion: Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models.