Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors

作者：Zhen Yuan, Xingyu Chen, Sisi Fan, Longfeng Chang, Linna Chu, Ying Zhang, Jie Wang, Shuang Li, Shuang Li, Jinxin Xie, HU Jian-guo, Runyu Miao, Lili Zhu, Zhenjiang Zhao, Honglin Li, Shiliang Li, Shiliang Li · 发表于：International Journal of Molecular Sciences · 年份：2024 · DOI：10.3390/ijms25010671 · 被引用次数：21 · 研究领域：Protein Tyrosine Phosphatases、Bioactive Compounds and Antitumor Agents、Galectins and Cancer Biology

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand–protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the ‘deformation energy’ of a ligand’s bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other...