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Issue 10, 2020
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Binding affinity and dissociation pathway predictions for a series of USP7 inhibitors with pyrimidinone scaffold by multiple computational methods

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Abstract

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.

Graphical abstract: Binding affinity and dissociation pathway predictions for a series of USP7 inhibitors with pyrimidinone scaffold by multiple computational methods

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Supplementary files

Article information


Submitted
22 Jan 2020
Accepted
15 Feb 2020
First published
17 Feb 2020

Phys. Chem. Chem. Phys., 2020,22, 5487-5499
Article type
Paper

Binding affinity and dissociation pathway predictions for a series of USP7 inhibitors with pyrimidinone scaffold by multiple computational methods

Z. Wang, X. Wang, Y. Kang, H. Zhong, C. Shen, X. Yao, D. Cao and T. Hou, Phys. Chem. Chem. Phys., 2020, 22, 5487
DOI: 10.1039/D0CP00370K

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