Exploring the Conformational Landscape of Bioactive Small Molecules

By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug...

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Autores: Zivanovic, Sanja, Colizzi, Francesco, Moreno Fajardo, David Fernando, Hospital Gasch, Adam, Soliva, Robert, Orozco López, Modesto
Tipo de recurso: artículo
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:2445/179129
Acceso en línea:https://hdl.handle.net/2445/179129
Access Level:acceso abierto
Palabra clave:Teoria quàntica
Molècules
Química combinatòria
Quantum theory
Molecules
Combinatorial chemistry
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spelling Exploring the Conformational Landscape of Bioactive Small MoleculesZivanovic, SanjaColizzi, FrancescoMoreno Fajardo, David FernandoHospital Gasch, AdamSoliva, RobertOrozco López, ModestoTeoria quànticaMolèculesQuímica combinatòriaQuantum theoryMoleculesCombinatorial chemistryBy using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the bioactiveconformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation.American Chemical Society2021202120202021info:eu-repo/semantics/article10 p.application/pdfhttps://hdl.handle.net/2445/179129Articles publicats en revistes (Bioquímica i Biomedicina Molecular)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/10.1021/acs.jctc.0c00304Journal Of Chemical Theory And Computation, 2020, 16, 10, 6575-6585https://doi.org/10.1021/acs.jctc.0c00304info:eu-repo/grantAgreement/EC/H2020/752415info:eu-repo/grantAgreement/EC/H2020/823830(c) American Chemical Society, 2020info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1791292026-05-29T05:05:01Z
dc.title.none.fl_str_mv Exploring the Conformational Landscape of Bioactive Small Molecules
title Exploring the Conformational Landscape of Bioactive Small Molecules
spellingShingle Exploring the Conformational Landscape of Bioactive Small Molecules
Zivanovic, Sanja
Teoria quàntica
Molècules
Química combinatòria
Quantum theory
Molecules
Combinatorial chemistry
title_short Exploring the Conformational Landscape of Bioactive Small Molecules
title_full Exploring the Conformational Landscape of Bioactive Small Molecules
title_fullStr Exploring the Conformational Landscape of Bioactive Small Molecules
title_full_unstemmed Exploring the Conformational Landscape of Bioactive Small Molecules
title_sort Exploring the Conformational Landscape of Bioactive Small Molecules
dc.creator.none.fl_str_mv Zivanovic, Sanja
Colizzi, Francesco
Moreno Fajardo, David Fernando
Hospital Gasch, Adam
Soliva, Robert
Orozco López, Modesto
author Zivanovic, Sanja
author_facet Zivanovic, Sanja
Colizzi, Francesco
Moreno Fajardo, David Fernando
Hospital Gasch, Adam
Soliva, Robert
Orozco López, Modesto
author_role author
author2 Colizzi, Francesco
Moreno Fajardo, David Fernando
Hospital Gasch, Adam
Soliva, Robert
Orozco López, Modesto
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Teoria quàntica
Molècules
Química combinatòria
Quantum theory
Molecules
Combinatorial chemistry
topic Teoria quàntica
Molècules
Química combinatòria
Quantum theory
Molecules
Combinatorial chemistry
description By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the bioactiveconformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/179129
url https://hdl.handle.net/2445/179129
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/10.1021/acs.jctc.0c00304
Journal Of Chemical Theory And Computation, 2020, 16, 10, 6575-6585
https://doi.org/10.1021/acs.jctc.0c00304
info:eu-repo/grantAgreement/EC/H2020/752415
info:eu-repo/grantAgreement/EC/H2020/823830
dc.rights.none.fl_str_mv (c) American Chemical Society, 2020
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Chemical Society, 2020
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
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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score 15.812429

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