Structure-based virtual screening has become a standard approach in modern drug discovery. It involves molecular docking and estimation of the ligand binding likelihood based on the scoring function. Surprisingly, in the search for new pharmaceuticals, one of the bottlenecks can be the ligand’s 3D structure prediction, especially for molecules with amine groups. In our work, the impact of the nitrogen atom hybridization in arylpiperazine derivatives on the results of docking to serotonin receptor type 7 is discussed. Our docking/re-docking studies show that the nitrogen lone pair may be involved in weak ligand–protein interactions. The presented results suggest that assumption of amine group planarity in the arylpiperazine 3D structure prediction may be a misleading factor in computer-aided drug discovery, influencing active conformation prediction. With our paper, we would like to raise awareness that in the case of compounds with amine groups, special care must be taken in the 3D ligand’s structure preparation for molecular docking studies.

中文翻译：

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平的还是有角的？以氮原子杂化对芳基哌嗪衍生物对接结果的影响为例

基于结构的虚拟筛选已成为现代药物发现的标准方法。它涉及基于评分函数的分子对接和配体结合可能性的估计。令人惊讶的是，在寻找新药物时，瓶颈之一可能是配体的 3D 结构预测，尤其是对于具有胺基的分子。在我们的工作中，讨论了芳基哌嗪衍生物中氮原子杂交对对接 7 型血清素受体结果的影响。我们的对接/重新对接研究表明，氮孤对可能参与弱配体-蛋白质相互作用。所呈现的结果表明，芳基哌嗪 3D 结构预测中胺基平面性的假设可能是计算机辅助药物发现中的误导因素，影响活性构象预测。通过我们的论文，我们想提高人们的认识，即对于具有胺基团的化合物，必须特别注意分子对接研究的 3D 配体结构准备。