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Inhibitory mechanism of 17β-aminoestrogens in the formation of Aβ aggregates

  • Lisset Noriega
  • Alfonso Díaz
  • Daniel Limón
  • María Eugenia Castro
  • Norma A. Caballero
  • Ramsés E. Ramírez
  • Jose Manuel Perez-AguilarEmail author
  • Francisco J. MelendezEmail author
Original Paper
Part of the following topical collections:
  1. QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aβ) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aβ1–40 and Aβ1–42 peptides, albeit the eleven-residue Aβ25–35 segment is largely used in biological studies because it retains the neurotoxic properties of the longer Aβ peptides. Recent studies indicate that treatment with therapeutic steroid hormones reduces the progress of the disease in AD models. Particularly, treatment with 17β-aminoestrogens (AEs) has shown a significant alleviation of the AD development by inhibiting oxidative stress and neuronal death. Yet, the mechanism by which the AE molecules exhibit their beneficial effects remains speculative. To shed light into the molecular mechanism of inhibition of the AD development by AEs, we investigated the possibility of direct interaction with the Aβ25–35 peptide. First, we calculate various interacting electronic properties of three AE derivatives as follows: prolame, butolame, and pentolame by performing DFT calculations. To account for the polymorphic nature of the Aβ aggregates, we considered four different Aβ25–35 systems extracted from AD relevant fibril structures. From the calculation of different electron density properties, specific interacting loci were identified that guided the construction and optimization of various complexes. Interestingly, the results suggest a similar inhibitory mechanism based on the direct interaction between the AEs and the M35 residue that seems to be general and independent of the polymorphic properties of the Aβ aggregates. Our analysis of the complex formation provides a structural framework for understanding the AE therapeutic properties in the molecular inhibitory mechanism of Aβ aggregation.

Keywords

Alzheimer’s disease Aβ peptide aggregation Aminoestrogens DFT Aβ fibril 

Notes

Acknowledgments

Authors acknowledge computer resources and support by the Laboratorio Nacional de Supercómputo del Sureste de México (LNS), the CONACyT member of the network of national laboratories, to the project 100256733-VIEP 2019 (BUAP, Mexico), and the PRODEP Academic Group BUAP-CA-263 (SEP, Mexico). F.J.M. acknowledges the computer resources of the Laboratorio de Supercómputo y Visualización en Paralelo at the Universidad Autónoma Metropolitana-Iztapalapa (UAM-I, Mexico).

Funding information

L.N. would like to thank the CONACyT (Mexico) for financial support (PhD fellowship CVU: 697889).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Lisset Noriega
    • 1
  • Alfonso Díaz
    • 2
  • Daniel Limón
    • 3
  • María Eugenia Castro
    • 4
  • Norma A. Caballero
    • 5
  • Ramsés E. Ramírez
    • 6
  • Jose Manuel Perez-Aguilar
    • 1
    Email author
  • Francisco J. Melendez
    • 1
    Email author
  1. 1.Laboratorio de Química Teórica, Centro de Investigación. Depto. de Fisicoquímica, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  2. 2.Departamento de Farmacia, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  3. 3.Laboratorio de Neurofarmacología, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  4. 4.Centro de Química, Instituto de CienciasBenemérita Universidad Autónoma de PueblaPueblaMexico
  5. 5.Facultad de Ciencias BiológicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  6. 6.Departamento de Fisicomatemáticas, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico

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