Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors
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Published:2024-01-04
Issue:1
Volume:25
Page:671
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Yuan Zhen1ORCID, Chen Xingyu1, Fan Sisi1, Chang Longfeng1, Chu Linna1, Zhang Ying1, Wang Jie1, Li Shuang1, Xie Jinxin1, Hu Jianguo1, Miao Runyu1, Zhu Lili1, Zhao Zhenjiang1, Li Honglin123, Li Shiliang12ORCID
Affiliation:
1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China 2. Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai 200062, China 3. Lingang Laboratory, Shanghai 200031, China
Abstract
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 widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).
Funder
National Key R&D Program of China National Natural Science Foundation of China Lingang Laboratory Fundamental Research Funds for the Central Universities Shanghai Rising-Star Program National Program for Special Supports of Eminent Professionals and the National Program for Support of Top-Notch Young Professionals
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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