Jedwabny Wiktoria, Dyguda-Kazimierowicz Edyta
Department of Chemistry, Wrocław University of Science and Technology, Wrocław, Poland.
J Mol Model. 2019 Jan 7;25(2):29. doi: 10.1007/s00894-018-3897-z.
Halogenated ligands are nowadays commonly designed in order to increase their potency against protein targets. Although novel computational methods of evaluating the affinity of such halogenated inhibitors have emerged, they still lack the sufficient accuracy, which is especially noticeable in the case of empirical scoring functions, being the method of choice in the drug design process. Here, we evaluated a series of halogenated inhibitors of phosphodiesterase type 5 with ab initio methods, revealing the physical nature of ligand binding and determining the components of interaction energy that are essential for proper inhibitor ranking. In particular, a nonempirical scoring model combining long-range contributions to the interaction energy provided a significant correlation with experimental binding potency, outperforming a number of commonly used empirical scoring functions. Considering the low computational cost associated with remarkable predictive abilities of the aforementioned model, it could be used for rapid assessment of the ligand affinity in the process of rational design of novel halogenated compounds.
如今，卤代配体通常被设计用于提高其对蛋白质靶点的效力。尽管已经出现了评估此类卤代抑制剂亲和力的新型计算方法，但它们仍缺乏足够的准确性，这在经验评分函数的情况下尤为明显，而经验评分函数是药物设计过程中的首选方法。在此，我们用从头算方法评估了一系列5型磷酸二酯酶的卤代抑制剂，揭示了配体结合的物理本质，并确定了对抑制剂正确排序至关重要的相互作用能成分。特别是，一个结合了对相互作用能的长程贡献的非经验评分模型与实验结合效力具有显著相关性，优于许多常用的经验评分函数。考虑到上述模型具有显著的预测能力且计算成本较低，它可用于在新型卤代化合物的合理设计过程中快速评估配体亲和力。
