Departament de Química Física i Analítica, Universitat Jaume I, Av. de Vicent Sos Baynat, s/n 12071, Castellón, Spain.
J Comput Aided Mol Des. 2018 May;32(5):607-622. doi: 10.1007/s10822-018-0114-1. Epub 2018 Mar 26.
In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.
在本研究中，基于混合量子力学和分子力学势，采用自由能微扰方法计算了一系列 huprines 与乙酰胆碱酯酶 (AChE) 的结合自由能。结合自由能计算和几何参数分析突出了 huprines 在 AChE 抑制中的立体化学的重要性。计算结合同位素效应以揭示配体与 AChE 峡谷之间的相互作用。提供了新的化学见解，以解释和合理化实验结果。对于具有中等酶亲和力差异的抑制剂家族，发现与实验数据具有良好的相关性。几何参数和每个残基相互作用能的分析表明，Asp72、Glu199 和 His440 对活性位点残基之间的相互作用网络有重要贡献，这些残基将抑制剂稳定在峡谷中。似乎峡谷残基的协同作用决定了酶对这些抑制剂的亲和力，其中 Asp72、Glu199 和 His440 有突出贡献。
