Binding affinity and dissociation pathway predictions for a series of USP7 inhibitors with pyrimidinone scaffold by multiple computational methods
| Autor: | Dong-Sheng Cao, Zhe Wang, Haiyang Zhong, Xuwen Wang, Chao Shen, Xiao-Jun Yao, Yu Kang, Tingjun Hou |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Scaffold 010304 chemical physics Chemistry General Physics and Astronomy Pyrimidinones Computational biology Plasma protein binding 01 natural sciences Ubiquitin-Specific Peptidase 7 03 medical and health sciences Computational Chemistry Protein structure Docking (molecular) Drug Design 0103 physical sciences Ubiquitin specific protease Enzyme Inhibitors Physical and Theoretical Chemistry Umbrella sampling Protein Binding 030304 developmental biology Dissociation pathway |
| Zdroj: | Physical Chemistry Chemical Physics. 22:5487-5499 |
| ISSN: | 1463-9084 1463-9076 |
| DOI: | 10.1039/d0cp00370k |
| Popis: | Ubiquitin specific protease 7 (USP7) has attracted increasing attention because of its multifaceted roles in different tumor types. The crystal structures of USP7-inhibitor complexes resolved recently provide reliable models for computational structure-based drug design (SBDD) towards USP7. How to accurately estimate USP7-ligand binding affinity is quite critical to guarantee the reliability of SBDD. In this study, we assessed the reliability of multiple computational methods to the binding affinity prediction for a series of USP7 inhibitors with the pyrimidinone scaffold, including molecular docking scoring, MM/PB(GB)SA, and umbrella sampling (US). It was found that the accuracy of the evaluated computational methods for binding affinity prediction follows the order: US-based method > MM/PB(GB)SA > Glide XP scoring. The calculation results demonstrate that incorporating protein flexibility through induced-fit docking or ensemble docking cannot improve the performance of the Glide scoring based on rigid-receptor docking. For the MM/PB(GB)SA methods, the choice of the protein structure and the calculation procedure has a marked impact on the predictions. More importantly, we discovered for the first time that there are significant differences in the dissociation pathways of strong-binding inhibitors and weak-binding inhibitors of USP7, which may be used as a new criterion to judge whether an inhibitor is a strong binder or not. It is expected that our work can provide valuable guidance on the design and discovery of potent USP7 inhibitors. |
| Databáze: | OpenAIRE |
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