New mimetic peptides inhibitors of Aβ aggregation: Molecular guidance for rational drug design

E.E. Barrera Guisasola, S. Andujar, E. Hubin, Kerensa Broersen, Yvonne M. Kraan, L. Mendez, C.M.L. Delpiccolo, M.F. Masman, A.M. Rodriguez, R.D. Enriz

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.
Original languageEnglish
Pages (from-to)136-152
Number of pages17
JournalEuropean journal of medicinal chemistry
Volume95
DOIs
Publication statusPublished - 2015

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Drug Design
Molecular Dynamics Simulation
Agglomeration
Peptides
Transmission Electron Microscopy
Hydrophobic and Hydrophilic Interactions
Pharmaceutical Preparations
Molecular dynamics
Alzheimer Disease
Salts
Fluorescence
Ligands
Molecular modeling
Water
Computer simulation
Oligomers
Transmission electron microscopy
Molecules
Monitoring
thioflavin T

Keywords

  • IR-97490
  • METIS-311566

Cite this

Barrera Guisasola, E.E. ; Andujar, S. ; Hubin, E. ; Broersen, Kerensa ; Kraan, Yvonne M. ; Mendez, L. ; Delpiccolo, C.M.L. ; Masman, M.F. ; Rodriguez, A.M. ; Enriz, R.D. / New mimetic peptides inhibitors of Aβ aggregation : Molecular guidance for rational drug design. In: European journal of medicinal chemistry. 2015 ; Vol. 95. pp. 136-152.
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Barrera Guisasola, EE, Andujar, S, Hubin, E, Broersen, K, Kraan, YM, Mendez, L, Delpiccolo, CML, Masman, MF, Rodriguez, AM & Enriz, RD 2015, 'New mimetic peptides inhibitors of Aβ aggregation: Molecular guidance for rational drug design' European journal of medicinal chemistry, vol. 95, pp. 136-152. https://doi.org/10.1016/j.ejmech.2015.03.042

New mimetic peptides inhibitors of Aβ aggregation : Molecular guidance for rational drug design. / Barrera Guisasola, E.E.; Andujar, S.; Hubin, E.; Broersen, Kerensa; Kraan, Yvonne M.; Mendez, L.; Delpiccolo, C.M.L.; Masman, M.F.; Rodriguez, A.M.; Enriz, R.D.

In: European journal of medicinal chemistry, Vol. 95, 2015, p. 136-152.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - New mimetic peptides inhibitors of Aβ aggregation

T2 - Molecular guidance for rational drug design

AU - Barrera Guisasola, E.E.

AU - Andujar, S.

AU - Hubin, E.

AU - Broersen, Kerensa

AU - Kraan, Yvonne M.

AU - Mendez, L.

AU - Delpiccolo, C.M.L.

AU - Masman, M.F.

AU - Rodriguez, A.M.

AU - Enriz, R.D.

PY - 2015

Y1 - 2015

N2 - A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.

AB - A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.

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JF - European journal of medicinal chemistry

SN - 0223-5234

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