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Improving Conformer Generation for Small Rings and Macrocycles Based on Distance Geometry and Experimental Torsional-Angle Preferences.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-03-10 , DOI: 10.1021/acs.jcim.0c00025 Shuzhe Wang 1 , Jagna Witek 1 , Gregory A Landrum 2 , Sereina Riniker 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-03-10 , DOI: 10.1021/acs.jcim.0c00025 Shuzhe Wang 1 , Jagna Witek 1 , Gregory A Landrum 2 , Sereina Riniker 1
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The conformer generator ETKDG is a stochastic search method that utilizes distance geometry together with knowledge derived from experimental crystal structures. It has been shown to generate good conformers for acyclic, flexible molecules. This work builds on ETKDG to improve conformer generation of molecules containing small or large aliphatic (i.e., non-aromatic) rings. For one, we devise additional torsional-angle potentials to describe small aliphatic rings and adapt the previously developed potentials for acyclic bonds to facilitate the sampling of macrocycles. However, due to the larger number of degrees of freedom of macrocycles, the conformational space to sample is much broader than for small molecules, creating a challenge for conformer generators. We therefore introduce different heuristics to restrict the search space of macrocycles and bias the sampling toward more experimentally relevant structures. Specifically, we show the usage of elliptical geometry and customizable Coulombic interactions as heuristics. The performance of the improved ETKDG is demonstrated on test sets of diverse macrocycles and cyclic peptides. The code developed here will be incorporated into the 2020.03 release of the open-source cheminformatics library RDKit.
中文翻译：
基于距离几何和实验性扭转角偏好，改善了小环和大环的顺应子生成。
构象生成器ETKDG是一种随机搜索方法，利用距离几何以及从实验晶体结构获得的知识。已显示出可为无环柔性分子生成良好的构象异构体。这项工作建立在ETKDG的基础上，以改善包含小或大脂族（即非芳族）环的分子的构象异构体生成。首先，我们设计了额外的扭转角势来描述小的脂族环，并采用先前开发的非环键势来促进大环的采样。但是，由于大环自由度的增加，样品的构象空间比小分子要宽得多，这给构象生成器带来了挑战。因此，我们引入了不同的启发式方法来限制大环的搜索空间，并使采样偏向于更具实验意义的结构。具体来说，我们展示了椭圆几何和可定制库仑相互作用作为启发式方法的用法。改进的ETKDG的性能在各种大环化合物和环肽的测试装置上得到了证明。此处开发的代码将并入2020.03版开源化学信息库RDKit中。
更新日期：2020-03-10
中文翻译：
基于距离几何和实验性扭转角偏好，改善了小环和大环的顺应子生成。
构象生成器ETKDG是一种随机搜索方法，利用距离几何以及从实验晶体结构获得的知识。已显示出可为无环柔性分子生成良好的构象异构体。这项工作建立在ETKDG的基础上，以改善包含小或大脂族（即非芳族）环的分子的构象异构体生成。首先，我们设计了额外的扭转角势来描述小的脂族环，并采用先前开发的非环键势来促进大环的采样。但是，由于大环自由度的增加，样品的构象空间比小分子要宽得多，这给构象生成器带来了挑战。因此，我们引入了不同的启发式方法来限制大环的搜索空间，并使采样偏向于更具实验意义的结构。具体来说，我们展示了椭圆几何和可定制库仑相互作用作为启发式方法的用法。改进的ETKDG的性能在各种大环化合物和环肽的测试装置上得到了证明。此处开发的代码将并入2020.03版开源化学信息库RDKit中。
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