Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan.
J Comput Aided Mol Des. 2020 Jun;34(6):647-658. doi: 10.1007/s10822-020-00302-4. Epub 2020 Feb 27.
In this study, a new method is proposed for calculating the relative binding free energy between a ligand and a protein, derived from a free energy variational principle (FEVP). To address the shortcomings of the method used in our previous study, we incorporate the dynamical fluctuation of a ligand in the FEVP calculation. The present modified method is applied to the Pim-1-kinase-ligand system and also to the FKBP-ligand system as a comparison with our previous work. Any inhibitor of Pim-1 kinase is expected to function as an anti-cancer drug. Some improvements are observed in the results compared to the previous study. The present work also shows comparable or better results than approaches using a standard technique of binding free energy calculations, such as the LIE and the MM-PB/SA methods. The possibility of applying the present method in the drug discovery process is also discussed.
在这项研究中，我们提出了一种新的方法来计算配体与蛋白质之间的相对结合自由能，该方法源自自由能变分原理（FEVP）。为了解决我们之前研究中使用的方法的缺点，我们将配体的动力学波动纳入 FEVP 计算中。目前的改进方法应用于 Pim-1 激酶-配体系统，并与我们之前的工作进行了比较。预计 Pim-1 激酶的任何抑制剂都将作为抗癌药物发挥作用。与之前的研究相比，结果有了一些改进。与使用配体自由能计算标准技术（如 LIE 和 MM-PB/SA 方法）的方法相比，本工作也显示出了相当或更好的结果。本文还讨论了将该方法应用于药物发现过程的可能性。
