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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Main Authors:	Shuheng Huang, Linxin Chen, Hu Mei, Duo Zhang, Tingting Shi, Zuyin Kuang, Yu Heng, Lei Xu, Xianchao Pan
Format:	Article
Language:	English
Published:	MDPI AG 2020-04-01
Series:	International Journal of Molecular Sciences
Subjects:	VolSurf dissociation rate constant Partial Least Squares prediction
Online Access:	https://www.mdpi.com/1422-0067/21/7/2456

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spelling	doaj-0d99f6850f32454e81eb5f0de7d483102020-11-25T02:33:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212456245610.3390/ijms21072456In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf MethodShuheng Huang0Linxin Chen1Hu Mei2Duo Zhang3Tingting Shi4Zuyin Kuang5Yu Heng6Lei Xu7Xianchao Pan8Key Laboratory of Biorheological Science and Technology (Ministry of Education), Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaCollege of Bioengineering, Chongqing University, Chongqing 400044, ChinaAccumulated 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 <i>k<sub>off</sub></i> 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.https://www.mdpi.com/1422-0067/21/7/2456VolSurfdissociation rate constantPartial Least Squaresprediction
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Shuheng Huang Linxin Chen Hu Mei Duo Zhang Tingting Shi Zuyin Kuang Yu Heng Lei Xu Xianchao Pan
spellingShingle	Shuheng Huang Linxin Chen Hu Mei Duo Zhang Tingting Shi Zuyin Kuang Yu Heng Lei Xu Xianchao Pan In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method International Journal of Molecular Sciences VolSurf dissociation rate constant Partial Least Squares prediction
author_facet	Shuheng Huang Linxin Chen Hu Mei Duo Zhang Tingting Shi Zuyin Kuang Yu Heng Lei Xu Xianchao Pan
author_sort	Shuheng Huang
title	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_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_sort	in silico prediction of the dissociation rate constants of small chemical ligands by 3d-grid-based volsurf method
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2020-04-01
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 <i>k<sub>off</sub></i> 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.
topic	VolSurf dissociation rate constant Partial Least Squares prediction
url	https://www.mdpi.com/1422-0067/21/7/2456
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In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method

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