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In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method

Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, th...

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Autores principales: Huang, Shuheng, Chen, Linxin, Mei, Hu, Zhang, Duo, Shi, Tingting, Kuang, Zuyin, Heng, Yu, Xu, Lei, Pan, Xianchao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177943/
https://www.ncbi.nlm.nih.gov/pubmed/32252223
http://dx.doi.org/10.3390/ijms21072456
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author Huang, Shuheng
Chen, Linxin
Mei, Hu
Zhang, Duo
Shi, Tingting
Kuang, Zuyin
Heng, Yu
Xu, Lei
Pan, Xianchao
author_facet Huang, Shuheng
Chen, Linxin
Mei, Hu
Zhang, Duo
Shi, Tingting
Kuang, Zuyin
Heng, Yu
Xu, Lei
Pan, Xianchao
author_sort Huang, Shuheng
collection PubMed
description Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, the VolSurf method was successfully applied to quantitatively predict the k(off) values of the small ligands of heat shock protein 90α (HSP90α), adenosine receptor (AR) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that few VolSurf descriptors can efficiently capture the key ligand surface properties related to dissociation rate; the resulting models demonstrated to be extremely simple, robust and predictive in comparison with available prediction methods. Therefore, it can be concluded that the VolSurf-based prediction method can be widely applied in the ligand-receptor binding kinetics and de novo drug design researches.
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spelling pubmed-71779432020-04-28 In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method Huang, Shuheng Chen, Linxin Mei, Hu Zhang, Duo Shi, Tingting Kuang, Zuyin Heng, Yu Xu, Lei Pan, Xianchao Int J Mol Sci Article Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, the VolSurf method was successfully applied to quantitatively predict the k(off) values of the small ligands of heat shock protein 90α (HSP90α), adenosine receptor (AR) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that few VolSurf descriptors can efficiently capture the key ligand surface properties related to dissociation rate; the resulting models demonstrated to be extremely simple, robust and predictive in comparison with available prediction methods. Therefore, it can be concluded that the VolSurf-based prediction method can be widely applied in the ligand-receptor binding kinetics and de novo drug design researches. MDPI 2020-04-02 /pmc/articles/PMC7177943/ /pubmed/32252223 http://dx.doi.org/10.3390/ijms21072456 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Shuheng
Chen, Linxin
Mei, Hu
Zhang, Duo
Shi, Tingting
Kuang, Zuyin
Heng, Yu
Xu, Lei
Pan, Xianchao
In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title_full In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title_fullStr In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title_full_unstemmed In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title_short In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method
title_sort in silico prediction of the dissociation rate constants of small chemical ligands by 3d-grid-based volsurf method
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177943/
https://www.ncbi.nlm.nih.gov/pubmed/32252223
http://dx.doi.org/10.3390/ijms21072456
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