Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.

Fragment-based drug discovery (FBDD) has been popular in the last decade, but some drawbacks, such as protein denaturation or ligand aggregation, have not yet clearly overcome in the framework of biomolecular simulations. In this work a systematic and semi-automatic method is presented as a novel pr...

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Autores: Privat-Contreras, Cristian, Granadino Roldán, José M., Bonet, Jordi, Santos Tomas, M., Pérez González, Juan J., Rubio Martínez, Jaime
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/188360
Acceso en línea:https://hdl.handle.net/2445/188360
Access Level:acceso abierto
Palabra clave:Dinàmica molecular
Disseny de medicaments
Molecular dynamics
Drug design
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spelling Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.Privat-Contreras, CristianGranadino Roldán, José M.Bonet, JordiSantos Tomas, M.Pérez González, Juan J.Rubio Martínez, JaimeDinàmica molecularDisseny de medicamentsMolecular dynamicsDrug designFragment-based drug discovery (FBDD) has been popular in the last decade, but some drawbacks, such as protein denaturation or ligand aggregation, have not yet clearly overcome in the framework of biomolecular simulations. In this work a systematic and semi-automatic method is presented as a novel proposal, named fragment dissolved Molecular Dynamics (fdMD), to improve research in future FBDD projects. Our method employs simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the object of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing this way denaturation of the target, while simultaneously generating a database of ligand-solvated boxes that can be used with other targets. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means of trustfully discard spurious binding sites. To test our method, four sets of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 μs when needed. The reported results point that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. Among the proposed descriptors, average MMGBSA and average KDEEP energies emerge as the most robust ones.Royal Society of Chemistry2022202220202022info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion12 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/188360Articles publicats en revistes (Ciència dels Materials i Química Física)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1039/D0CP05471BPhysical Chemistry Chemical Physics, 2020, vol. 23, p. 3123-3134https://doi.org/10.1039/D0CP05471B(c) Privat-Contreras, Cristian et al., 2020info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1883602026-05-29T05:05:01Z
dc.title.none.fl_str_mv Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
title Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
spellingShingle Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
Privat-Contreras, Cristian
Dinàmica molecular
Disseny de medicaments
Molecular dynamics
Drug design
title_short Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
title_full Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
title_fullStr Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
title_full_unstemmed Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
title_sort Fragment Dissolved molecular dynamics: A systematic and efficient method to locate binding sites.
dc.creator.none.fl_str_mv Privat-Contreras, Cristian
Granadino Roldán, José M.
Bonet, Jordi
Santos Tomas, M.
Pérez González, Juan J.
Rubio Martínez, Jaime
author Privat-Contreras, Cristian
author_facet Privat-Contreras, Cristian
Granadino Roldán, José M.
Bonet, Jordi
Santos Tomas, M.
Pérez González, Juan J.
Rubio Martínez, Jaime
author_role author
author2 Granadino Roldán, José M.
Bonet, Jordi
Santos Tomas, M.
Pérez González, Juan J.
Rubio Martínez, Jaime
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Dinàmica molecular
Disseny de medicaments
Molecular dynamics
Drug design
topic Dinàmica molecular
Disseny de medicaments
Molecular dynamics
Drug design
description Fragment-based drug discovery (FBDD) has been popular in the last decade, but some drawbacks, such as protein denaturation or ligand aggregation, have not yet clearly overcome in the framework of biomolecular simulations. In this work a systematic and semi-automatic method is presented as a novel proposal, named fragment dissolved Molecular Dynamics (fdMD), to improve research in future FBDD projects. Our method employs simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the object of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing this way denaturation of the target, while simultaneously generating a database of ligand-solvated boxes that can be used with other targets. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means of trustfully discard spurious binding sites. To test our method, four sets of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 μs when needed. The reported results point that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. Among the proposed descriptors, average MMGBSA and average KDEEP energies emerge as the most robust ones.
publishDate 2020
dc.date.none.fl_str_mv 2020
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/188360
url https://hdl.handle.net/2445/188360
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1039/D0CP05471B
Physical Chemistry Chemical Physics, 2020, vol. 23, p. 3123-3134
https://doi.org/10.1039/D0CP05471B
dc.rights.none.fl_str_mv (c) Privat-Contreras, Cristian et al., 2020
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Privat-Contreras, Cristian et al., 2020
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
dc.source.none.fl_str_mv Articles publicats en revistes (Ciència dels Materials i Química Física)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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