eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations

C.L. Capoferri, Marc van Dijk, A.S. Rustenburg, Tsjerk Wassenaar, D.P. Kooi, E.A. Rifai, N.P.E. Vermeulen, D.P. Geerke

Research output: Contribution to journalArticle

Abstract


Background

Computational methods to predict binding affinities of small ligands toward relevant biological (off-)targets are helpful in prioritizing the screening and synthesis of new drug candidates, thereby speeding up the drug discovery process. However, use of ligand-based approaches can lead to erroneous predictions when structural and dynamic features of the target substantially affect ligand binding. Free energy methods for affinity computation can include steric and electrostatic protein–ligand interactions, solvent effects, and thermal fluctuations, but often they are computationally demanding and require a high level of supervision. As a result their application is typically limited to the screening of small sets of compounds by experts in molecular modeling.
Results

We have developed eTOX ALLIES, an open source framework that allows the automated prediction of ligand-binding free energies requiring the ligand structure as only input. eTOX ALLIES is based on the linear interaction energy approach, an efficient end-point free energy method derived from Free Energy Perturbation theory. Upon submission of a ligand or dataset of compounds, the tool performs the multiple steps required for binding free-energy prediction (docking, ligand topology creation, molecular dynamics simulations, data analysis), making use of external open source software where necessary. Moreover, functionalities are also available to enable and assist the creation and calibration of new models. In addition, a web graphical user interface has been developed to allow use of free-energy based models to users that are not an expert in molecular modeling.
Conclusions

Because of the user-friendliness, efficiency and free-software licensing, eTOX ALLIES represents a novel extension of the toolbox for computational chemists, pharmaceutical scientists and toxicologists, who are interested in fast affinity predictions of small molecules toward biological (off-)targets for which protein flexibility, solvent and binding site interactions directly affect the strength of ligand-protein binding.
LanguageEnglish
Pages1-13
Number of pages13
JournalJournal of Cheminformatics
Volume9
Issue number58
DOIs
StatePublished - 2017

Cite this

@article{7a0ea877e4fc413c9a5c0f45740eab7d,
title = "eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations",
abstract = "BackgroundComputational methods to predict binding affinities of small ligands toward relevant biological (off-)targets are helpful in prioritizing the screening and synthesis of new drug candidates, thereby speeding up the drug discovery process. However, use of ligand-based approaches can lead to erroneous predictions when structural and dynamic features of the target substantially affect ligand binding. Free energy methods for affinity computation can include steric and electrostatic protein–ligand interactions, solvent effects, and thermal fluctuations, but often they are computationally demanding and require a high level of supervision. As a result their application is typically limited to the screening of small sets of compounds by experts in molecular modeling.ResultsWe have developed eTOX ALLIES, an open source framework that allows the automated prediction of ligand-binding free energies requiring the ligand structure as only input. eTOX ALLIES is based on the linear interaction energy approach, an efficient end-point free energy method derived from Free Energy Perturbation theory. Upon submission of a ligand or dataset of compounds, the tool performs the multiple steps required for binding free-energy prediction (docking, ligand topology creation, molecular dynamics simulations, data analysis), making use of external open source software where necessary. Moreover, functionalities are also available to enable and assist the creation and calibration of new models. In addition, a web graphical user interface has been developed to allow use of free-energy based models to users that are not an expert in molecular modeling.ConclusionsBecause of the user-friendliness, efficiency and free-software licensing, eTOX ALLIES represents a novel extension of the toolbox for computational chemists, pharmaceutical scientists and toxicologists, who are interested in fast affinity predictions of small molecules toward biological (off-)targets for which protein flexibility, solvent and binding site interactions directly affect the strength of ligand-protein binding.",
author = "C.L. Capoferri and {van Dijk}, Marc and A.S. Rustenburg and Tsjerk Wassenaar and D.P. Kooi and E.A. Rifai and N.P.E. Vermeulen and D.P. Geerke",
year = "2017",
doi = "10.1186/s13321-017-0243-x",
language = "English",
volume = "9",
pages = "1--13",
journal = "Journal of Cheminformatics",
issn = "1758-2946",
publisher = "Chemistry Central",
number = "58",

}

eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations. / Capoferri, C.L.; van Dijk, Marc; Rustenburg, A.S.; Wassenaar, Tsjerk; Kooi, D.P.; Rifai, E.A.; Vermeulen, N.P.E.; Geerke, D.P.

In: Journal of Cheminformatics, Vol. 9, No. 58, 2017, p. 1-13.

Research output: Contribution to journalArticle

TY - JOUR

T1 - eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations

AU - Capoferri,C.L.

AU - van Dijk,Marc

AU - Rustenburg,A.S.

AU - Wassenaar,Tsjerk

AU - Kooi,D.P.

AU - Rifai,E.A.

AU - Vermeulen,N.P.E.

AU - Geerke,D.P.

PY - 2017

Y1 - 2017

N2 - BackgroundComputational methods to predict binding affinities of small ligands toward relevant biological (off-)targets are helpful in prioritizing the screening and synthesis of new drug candidates, thereby speeding up the drug discovery process. However, use of ligand-based approaches can lead to erroneous predictions when structural and dynamic features of the target substantially affect ligand binding. Free energy methods for affinity computation can include steric and electrostatic protein–ligand interactions, solvent effects, and thermal fluctuations, but often they are computationally demanding and require a high level of supervision. As a result their application is typically limited to the screening of small sets of compounds by experts in molecular modeling.ResultsWe have developed eTOX ALLIES, an open source framework that allows the automated prediction of ligand-binding free energies requiring the ligand structure as only input. eTOX ALLIES is based on the linear interaction energy approach, an efficient end-point free energy method derived from Free Energy Perturbation theory. Upon submission of a ligand or dataset of compounds, the tool performs the multiple steps required for binding free-energy prediction (docking, ligand topology creation, molecular dynamics simulations, data analysis), making use of external open source software where necessary. Moreover, functionalities are also available to enable and assist the creation and calibration of new models. In addition, a web graphical user interface has been developed to allow use of free-energy based models to users that are not an expert in molecular modeling.ConclusionsBecause of the user-friendliness, efficiency and free-software licensing, eTOX ALLIES represents a novel extension of the toolbox for computational chemists, pharmaceutical scientists and toxicologists, who are interested in fast affinity predictions of small molecules toward biological (off-)targets for which protein flexibility, solvent and binding site interactions directly affect the strength of ligand-protein binding.

AB - BackgroundComputational methods to predict binding affinities of small ligands toward relevant biological (off-)targets are helpful in prioritizing the screening and synthesis of new drug candidates, thereby speeding up the drug discovery process. However, use of ligand-based approaches can lead to erroneous predictions when structural and dynamic features of the target substantially affect ligand binding. Free energy methods for affinity computation can include steric and electrostatic protein–ligand interactions, solvent effects, and thermal fluctuations, but often they are computationally demanding and require a high level of supervision. As a result their application is typically limited to the screening of small sets of compounds by experts in molecular modeling.ResultsWe have developed eTOX ALLIES, an open source framework that allows the automated prediction of ligand-binding free energies requiring the ligand structure as only input. eTOX ALLIES is based on the linear interaction energy approach, an efficient end-point free energy method derived from Free Energy Perturbation theory. Upon submission of a ligand or dataset of compounds, the tool performs the multiple steps required for binding free-energy prediction (docking, ligand topology creation, molecular dynamics simulations, data analysis), making use of external open source software where necessary. Moreover, functionalities are also available to enable and assist the creation and calibration of new models. In addition, a web graphical user interface has been developed to allow use of free-energy based models to users that are not an expert in molecular modeling.ConclusionsBecause of the user-friendliness, efficiency and free-software licensing, eTOX ALLIES represents a novel extension of the toolbox for computational chemists, pharmaceutical scientists and toxicologists, who are interested in fast affinity predictions of small molecules toward biological (off-)targets for which protein flexibility, solvent and binding site interactions directly affect the strength of ligand-protein binding.

U2 - 10.1186/s13321-017-0243-x

DO - 10.1186/s13321-017-0243-x

M3 - Article

VL - 9

SP - 1

EP - 13

JO - Journal of Cheminformatics

T2 - Journal of Cheminformatics

JF - Journal of Cheminformatics

SN - 1758-2946

IS - 58

ER -