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Evaluating the conformational space of the active site of D2 dopamine receptor. Scope and limitations of the standard docking methods
Journal of Computational Chemistry ( IF 3 ) Pub Date : 2022-05-31 , DOI: 10.1002/jcc.26938
Rodrigo D Tosso 1 , M Natalia C Zarycz 1 , Ayelén Schiel 1 , Luisa Goicoechea Moro 1 , Héctor A Baldoni 2 , Emilio Angelina 3 , Ricardo D Enriz 1
Affiliation  

We report here for the first time the potential energy surfaces (PES) of phenyletilamine (PEA) and meta-tyramine (m-OH-PEA) at the D2 dopamine receptor (D2DR) binding site. PESs not only allow us to observe all the critical points of the surface (minimums, maximums, and transition states), but also to note the ease or difficulty that each local minima have for their conformational inter-conversions and therefore know the conformational flexibility that these ligands have in their active sites. Taking advantage of possessing this valuable information, we analyze how accurate a standard docking study is in these cases. Our results indicate that although we have to be careful in how to carry out this type of study and to consider performing some extra-simulations, docking calculations can be satisfactory. In order to analyze in detail the different molecular interactions that are stabilizing the different ligand-receptor (L-R) complexes, we carried out quantum theory of atoms in molecules (QTAIM) computations and NMR shielding calculations. Although some of these techniques are a bit tedious and require more computational time, our results demonstrate the importance of performing computational simulations using different types of combined techniques (docking/MD/hybrid QM-MM/QTAIM and NMR shielding calculations) in order to obtain more accurate results. Our results allow us to understand in details the molecular interactions stabilizing and destabilizing the different L-R complexes reported here. Thus, the different activities observed for dopamine (DA), m-OH-PEA, and PEA can be clearly explained at molecular level.

中文翻译:

评估 D2 多巴胺受体活性位点的构象空间。标准对接方法的范围和限制

我们在这里首次报告苯乙胺 (PEA) 和间酪胺 (m-OH-PEA) 在 D 2处的势能表面 (PES)多巴胺受体 (D2DR) 结合位点。PES 不仅允许我们观察表面的所有临界点(最小值、最大值和过渡态),而且还可以注意到每个局部最小值对于它们的构象相互转换的难易程度,因此知道构象的灵活性这些配体在它们的活性位点中具有。利用拥有这些有价值的信息,我们分析了标准对接研究在这些情况下的准确性。我们的结果表明,虽然我们必须小心如何进行此类研究并考虑执行一些额外的模拟,但对接计算可以令人满意。为了详细分析稳定不同配体-受体 (LR) 复合物的不同分子相互作用,我们进行了分子中原子的量子理论(QTAIM)计算和核磁共振屏蔽计算。虽然其中一些技术有点乏味并且需要更多的计算时间,但我们的结果证明了使用不同类型的组合技术(对接/MD/混合 QM-MM/QTAIM 和 NMR 屏蔽计算)执行计算模拟的重要性,以获得更准确的结果。我们的结果使我们能够详细了解稳定和破坏此处报道的不同 LR 复合物的分子相互作用。因此,观察到的多巴胺 (DA)、m-OH-PEA 和 PEA 的不同活性可以在分子水平上清楚地解释。我们的结果证明了使用不同类型的组合技术(对接/MD/混合 QM-MM/QTAIM 和 NMR 屏蔽计算)进行计算模拟以获得更准确结果的重要性。我们的结果使我们能够详细了解稳定和破坏此处报道的不同 LR 复合物的分子相互作用。因此,观察到的多巴胺 (DA)、m-OH-PEA 和 PEA 的不同活性可以在分子水平上清楚地解释。我们的结果证明了使用不同类型的组合技术(对接/MD/混合 QM-MM/QTAIM 和 NMR 屏蔽计算)进行计算模拟以获得更准确结果的重要性。我们的结果使我们能够详细了解稳定和破坏此处报道的不同 LR 复合物的分子相互作用。因此,观察到的多巴胺 (DA)、m-OH-PEA 和 PEA 的不同活性可以在分子水平上清楚地解释。
更新日期:2022-05-31
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