IMIBIO-SL CONICET, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de Los Andes 950, 5700, San Luis, Argentina.
IMIBIO-SL CONICET, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de Los Andes 950, 5700, San Luis, Argentina.
Eur J Med Chem. 2020 Dec 15;208:112792. doi: 10.1016/j.ejmech.2020.112792. Epub 2020 Sep 6.
In medicinal chemistry, it is extremely important to evaluate, as accurately as possible, the molecular interactions involved in the formation of different ligand-receptor (L-R) complexes. Evaluating the different molecular interactions by quantum mechanics calculations is not a simple task, since formation of an L-R complex is a dynamic process. In this case, the use of combined techniques of molecular dynamics (MD) and quantum calculations is one the best possible approaches. In this work we report a comparative study using combined MD and QTAIM (Quantum Theory of Atoms In Molecules) calculations for five biological systems with different levels of structural complexity. We have studied Acetylcholinesterase (AChE), D2 Dopamine Receptor (D2DR), beta Secretase (BACE1), Dihydrofolate Reductase (DHFR) and Sphingosine Kinase 1 (SphK1). In these molecular targets, we have analyzed different ligands with diverse structural characteristics. The inhibitory activities of most of them have been previously measured in our laboratory. Our results indicate that QTAIM calculations can be extremely useful for in silico studies. It is possible to obtain very accurate information about the strength of the molecular interactions that stabilize the formation of the different L-R complexes. Better correlations can be obtained between theoretical and experimental data by using QTAIM calculations, allowing us to discriminate among ligands with similar affinities. QTAIM analysis gives fairly accurate information for weak interactions which are not well described by MD simulations. QTAIM study also allowed us to evaluate and determine which parts of the ligand need to be modified in order to increase its interactions with the molecular target. In this study we have discussed the importance of combined MD/QTAIM calculations for this type of simulations, showing their scopes and limitations.
在药物化学中，尽可能准确地评估形成不同配体-受体（L-R）复合物的分子相互作用是非常重要的。通过量子力学计算评估不同的分子相互作用并不是一件简单的任务，因为 L-R 复合物的形成是一个动态过程。在这种情况下，使用分子动力学（MD）和量子计算的组合技术是最好的方法之一。在这项工作中，我们报告了使用组合 MD 和 QTAIM（分子中的原子量子理论）计算对具有不同结构复杂性的五个生物系统进行的比较研究。我们研究了乙酰胆碱酯酶（AChE）、D2 多巴胺受体（D2DR）、β 分泌酶（BACE1）、二氢叶酸还原酶（DHFR）和鞘氨醇激酶 1（SphK1）。在这些分子靶标中，我们分析了具有不同结构特征的不同配体。它们中的大多数抑制剂的活性已在我们的实验室中进行了先前测量。我们的结果表明，QTAIM 计算对于计算机研究非常有用。可以获得有关稳定不同 L-R 复合物形成的分子相互作用强度的非常准确的信息。通过使用 QTAIM 计算，可以获得理论和实验数据之间更好的相关性，从而可以区分具有相似亲和力的配体。对于 MD 模拟不能很好描述的弱相互作用，QTAIM 分析可以提供相当准确的信息。QTAIM 研究还使我们能够评估和确定需要修改配体的哪些部分以增加其与分子靶标的相互作用。在这项研究中，我们讨论了组合 MD/QTAIM 计算对于这类模拟的重要性，展示了它们的范围和局限性。
