Reliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water
Reliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water
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DOI：
10.1021/acs.jcim.8b00151
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发表时间：
2018-05-01
影响因子：
5.6
通讯作者：
Goeller, Andreas H.
中科院分区：
文献类型：
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作者：
Cavasin, Anna Theresa;Hillisch, Alexander;Goeller, Andreas H.
通过定量构效关系和机器学习方法从结构预测化合物性质是小分子药物研究中的一项重要计算化学任务。虽然许多这样的属性是依赖于三维结构，甚至构象合奏，大多数模型是基于从二维结构衍生的描述符。在这里，我们提出了一个彻底的基准研究力场，半经验，和密度泛函方法的构象能量的计算在气相和水溶剂化的基础上正确识别相关的低能量构象。我们发现，紧密结合的抗体GFN-xTB显示出最低的误差指标和最高的相关性，基准PBEO-D3（BJ）/def 2-TZVP在气相中的计算快速的方法，并在溶剂OPLS 3变得相当的性能。MMFF 94、AM 1和DFTB+的性能较差，而性能优化但价格昂贵得多的功能性PBEH-3c产生的能量几乎与基准完全相关，应在经济实惠的情况下使用。在我们的研究结果的基础上，我们已经实现了一个可靠的和快速的协议，用于识别低能量构象的药物样分子在水中，可用于定量的应变能和熵的贡献，以目标结合，以及用于推导符合合奏依赖的分子描述符。
Prediction of compound properties from structure via quantitative structure-activity relationship and machine-learning approaches is an important computational chemistry task in small-molecule drug research. Though many such properties are dependent on three-dimensional structures or even conformer ensembles, the majority of models are based on descriptors derived from two-dimensional structures. Here we present results from a thorough benchmark study of force field, semiempirical, and density functional methods for the calculation of conformer energies in the gas phase and water solvation as a foundation for the correct identification of relevant low-energy conformers. We find that the tight-binding ansatz GFN-xTB shows the lowest error metrics and highest correlation to the benchmark PBEO-D3(BJ)/def2-TZVP in the gas phase for the computationally fast methods and that in solvent OPLS3 becomes comparable in performance. MMFF94, AM1, and DFTB+ perform worse, whereas the performance-optimized but far more expensive functional PBEh-3c yields energies almost perfectly correlated to the benchmark and should be used whenever affordable. On the basis of our findings, we have implemented a reliable and fast protocol for the identification of low-energy conformers of drug-like molecules in water that can be used for the quantification of strain energy and entropy contributions to target binding as well as for the derivation of conformer-ensemble-dependent molecular descriptors.