Virtual and in vitro screens reveal a potential pharmacophore that avoids the fibrillization of Aβ<inf>1-42</inf>

Maricarmen Hernández-Rodríguez, José Correa-Basurto, María Inés Nicolás-Vázquez, René Miranda-Ruvalcaba, Claudia Guadalupe Benítez-Cardoza, Aldo Arturo Reséndiz-Albor, Juan Vicente Méndez-Méndez, Martha C. Rosales-Hernández

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Abstract

© 2015 Hernández-Rodríguez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1-42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1-42pathological aggregation represents a field of research interest. Several Aβ1-42fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1-42in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1-42in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1-42aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.
Original languageAmerican English
JournalPLoS ONE
DOIs
StatePublished - 14 Jul 2015

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tertiary amines
protein aggregates
Amines
aromatic compounds
Conformations
Agglomeration
peptides
circular dichroism spectroscopy
Aptitude
atomic force microscopy
Atomic Force Microscopy
amyloid
Licensure
Alzheimer disease
Circular Dichroism
Oligomers
Amyloid
Free energy
Reproduction
Atomic force microscopy

Cite this

@article{945cd86762ad47d28ac5554c6800c5f4,
title = "Virtual and in vitro screens reveal a potential pharmacophore that avoids the fibrillization of Aβ1-42",
abstract = "{\circledC} 2015 Hern{\'a}ndez-Rodr{\'i}guez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1-42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1-42pathological aggregation represents a field of research interest. Several Aβ1-42fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1-42in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1-42in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1-42aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.",
author = "Maricarmen Hern{\'a}ndez-Rodr{\'i}guez and Jos{\'e} Correa-Basurto and Nicol{\'a}s-V{\'a}zquez, {Mar{\'i}a In{\'e}s} and Ren{\'e} Miranda-Ruvalcaba and Ben{\'i}tez-Cardoza, {Claudia Guadalupe} and Res{\'e}ndiz-Albor, {Aldo Arturo} and M{\'e}ndez-M{\'e}ndez, {Juan Vicente} and Rosales-Hern{\'a}ndez, {Martha C.}",
year = "2015",
month = "7",
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language = "American English",
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T1 - Virtual and in vitro screens reveal a potential pharmacophore that avoids the fibrillization of Aβ1-42

AU - Hernández-Rodríguez, Maricarmen

AU - Correa-Basurto, José

AU - Nicolás-Vázquez, María Inés

AU - Miranda-Ruvalcaba, René

AU - Benítez-Cardoza, Claudia Guadalupe

AU - Reséndiz-Albor, Aldo Arturo

AU - Méndez-Méndez, Juan Vicente

AU - Rosales-Hernández, Martha C.

PY - 2015/7/14

Y1 - 2015/7/14

N2 - © 2015 Hernández-Rodríguez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1-42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1-42pathological aggregation represents a field of research interest. Several Aβ1-42fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1-42in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1-42in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1-42aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.

AB - © 2015 Hernández-Rodríguez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1-42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1-42pathological aggregation represents a field of research interest. Several Aβ1-42fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1-42in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1-42in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1-42aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.

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DO - 10.1371/journal.pone.0130263

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