Diameter is a key 3D characteristic for assessments of efficient inhibitors of protein-protein interactions

Masakazu Nakadai; Shuta Tomida

doi:10.1021/acs.jcim.0c00607

Diameter is a key 3D characteristic for assessments of efficient inhibitors of protein-protein interactions

Masakazu Nakadai, Shuta Tomida

University Hospital

Research output: Contribution to journal › Article › peer-review

Abstract

Three-dimensional (3D) molecular descriptors, including physicochemical and shape properties, for protein-protein interaction (PPI) interface inhibitors have become a topic of discussion. However, the relationships between such properties and binding free energy have not been adequately investigated. In this study, we focused on identifying key 3D molecular descriptors related to the binding free energy and/or the ligand efficiency (LE) of PPI interface inhibitors. A positive correlation was found between the binding free energy and the diameter (D) of cylindrical 3D molecules, in addition to a correlation between LE and D/heavy atom count (HAC). In addition, we showed a correlation between LE and D/HAC for macrocyclic compounds, suggesting that the present findings could be applied during assessments of the potential of macrocyclic PPI interface inhibitors in drug discovery processes.

Original language	English
Pages (from-to)	4785-4790
Number of pages	6
Journal	Journal of Chemical Information and Modeling
Volume	60
Issue number	10
DOIs	https://doi.org/10.1021/acs.jcim.0c00607
Publication status	Published - Oct 26 2020

ASJC Scopus subject areas

Chemistry(all)
Chemical Engineering(all)
Computer Science Applications
Library and Information Sciences

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10.1021/acs.jcim.0c00607

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title = "Diameter is a key 3D characteristic for assessments of efficient inhibitors of protein-protein interactions",

abstract = "Three-dimensional (3D) molecular descriptors, including physicochemical and shape properties, for protein-protein interaction (PPI) interface inhibitors have become a topic of discussion. However, the relationships between such properties and binding free energy have not been adequately investigated. In this study, we focused on identifying key 3D molecular descriptors related to the binding free energy and/or the ligand efficiency (LE) of PPI interface inhibitors. A positive correlation was found between the binding free energy and the diameter (D) of cylindrical 3D molecules, in addition to a correlation between LE and D/heavy atom count (HAC). In addition, we showed a correlation between LE and D/HAC for macrocyclic compounds, suggesting that the present findings could be applied during assessments of the potential of macrocyclic PPI interface inhibitors in drug discovery processes.",

author = "Masakazu Nakadai and Shuta Tomida",

note = "Funding Information: This work was partially supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (B) for S.T.) grant number JP20H03771. ",

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