Tokuda Kana, Watanabe Chiduru, Okiyama Yoshio, Mochizuki Yuji, Fukuzawa Kaori, Komeiji Yuto
Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
J Mol Graph Model. 2016 Sep;69:144-53. doi: 10.1016/j.jmgm.2016.08.004. Epub 2016 Aug 31.
The fragment molecular orbital (FMO) method was applied to quantum chemical calculations of neuramic acid, the natural substrate of the influenza virus neuraminidase, and two of its competitive inhibitors, Oseltamivir (Tamiful(®)) and Zanamivir (Relenza(®)), to investigate their hydrated structures and energetics. Each of the three ligands was immersed in an explicit water solvent, geometry-optimized by classical MM and QM/MM methods, and subjected to FMO calculations with 2-, 3-, and 4-body corrections under several fragmentation options. The important findings were that QM/MM optimization was preferable to obtain reliable hydrated structures of the ligands, that the 3-body correction was important for quantitative evaluation of the solvation energy, and that the dehydration effect was most remarkable near the hydrophobic sections of the ligands. In addition, the hydration energy calculated by the explicit solvent was compared with the hydration free energy calculated by the implicit solvent via the Poisson-Boltzmann equation, and the two showed a fairly good correlation. These findings will serve as useful information for rapid drug design.
片段分子轨道（FMO）方法被应用于流感病毒神经氨酸酶的天然底物神经氨酸及其两种竞争性抑制剂奥司他韦（达菲®）和扎那米韦（瑞乐沙®）的量子化学计算，以研究它们的水合结构和能量学。将这三种配体中的每一种都浸入明确的水溶剂中，通过经典的分子力学（MM）和量子力学/分子力学（QM/MM）方法进行几何优化，并在几种片段划分选项下进行具有二体、三体和四体校正的FMO计算。重要的发现是，QM/MM优化对于获得可靠的配体水合结构是更可取的，三体校正在溶剂化能的定量评估中很重要，并且脱水效应在配体的疏水部分附近最为显著。此外，将通过明确溶剂计算的水合能与通过泊松-玻尔兹曼方程由隐式溶剂计算的水合自由能进行了比较，两者显示出相当好的相关性。这些发现将为快速药物设计提供有用的信息。
