Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits
The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the b...
| Autores: | , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/201914 |
| Acesso em linha: | https://hdl.handle.net/2445/201914 |
| Access Level: | acceso abierto |
| Palavra-chave: | Inhibidors enzimàtics Lligands Enzyme inhibitors Ligands |
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Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hitsVázquez, JavierGinex, TizianaHerrero, AlbertMorisseau, ChristopheHammock, Bruce D.Luque Garriga, F. XavierInhibidors enzimàticsLligandsEnzyme inhibitorsLigandsThe human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure−activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC50 < 20 nM, including two with IC50 values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site.American Chemical Society2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/201914Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1021/acs.jcim.3c00301Journal of Chemical Information and Modeling, 2023, vol. 63, p. 3209-3225https://doi.org/10.1021/acs.jcim.3c00301cc-by (c) Javier Vázquez, et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2019142026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| title |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| spellingShingle |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits Vázquez, Javier Inhibidors enzimàtics Lligands Enzyme inhibitors Ligands |
| title_short |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| title_full |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| title_fullStr |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| title_full_unstemmed |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| title_sort |
Screening and biological evaluation of soluble Epoxide Hydrolase inhibitors: Assessing the role of hydrophobicity in the pharmacophore-guided search of novel hits |
| dc.creator.none.fl_str_mv |
Vázquez, Javier Ginex, Tiziana Herrero, Albert Morisseau, Christophe Hammock, Bruce D. Luque Garriga, F. Xavier |
| author |
Vázquez, Javier |
| author_facet |
Vázquez, Javier Ginex, Tiziana Herrero, Albert Morisseau, Christophe Hammock, Bruce D. Luque Garriga, F. Xavier |
| author_role |
author |
| author2 |
Ginex, Tiziana Herrero, Albert Morisseau, Christophe Hammock, Bruce D. Luque Garriga, F. Xavier |
| author2_role |
author author author author author |
| dc.subject.none.fl_str_mv |
Inhibidors enzimàtics Lligands Enzyme inhibitors Ligands |
| topic |
Inhibidors enzimàtics Lligands Enzyme inhibitors Ligands |
| description |
The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure−activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC50 < 20 nM, including two with IC50 values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/201914 |
| url |
https://hdl.handle.net/2445/201914 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1021/acs.jcim.3c00301 Journal of Chemical Information and Modeling, 2023, vol. 63, p. 3209-3225 https://doi.org/10.1021/acs.jcim.3c00301 |
| dc.rights.none.fl_str_mv |
cc-by (c) Javier Vázquez, et al., 2023 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by (c) Javier Vázquez, et al., 2023 http://creativecommons.org/licenses/by/3.0/es/ |
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openAccess |
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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 (Nutrició, Ciències de l'Alimentació i Gastronomia) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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15,198674 |