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

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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.

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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

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

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Authors and Affiliations

  1. Laboratorio de Química Teórica, Centro de Investigación. Depto. de Fisicoquímica, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Edif 105-I, San Claudio y 22 Sur, Ciudad Universitaria, Col. San Manuel, 72570, Puebla, Mexico

    Lisset Noriega, Jose Manuel Perez-Aguilar & Francisco J. Melendez

  2. Departamento de Farmacia, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Av. San Claudio y 14 Sur, Col. San Manuel, 72570, Puebla, Mexico

    Alfonso Díaz

  3. Laboratorio de Neurofarmacología, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Av. San Claudio y 14 Sur, Col. San Manuel, 72570, Puebla, Mexico

    Daniel Limón

  4. Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Complejo de Ciencias, ICUAP, Edif. IC8, 22 Sur y San Claudio, Ciudad Universitaria, 72570, Puebla, Mexico

    María Eugenia Castro

  5. Facultad de Ciencias Biológicas, Benemérita Universidad Autónoma de Puebla, San Claudio y 14 Sur, Ciudad Universitaria, Col. San Manuel, 72570, Puebla, Mexico

    Norma A. Caballero

  6. Departamento de Fisicomatemáticas, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Edif 105-I, San Claudio y 22 Sur, Ciudad Universitaria, Col. San Manuel, 72570, Puebla, Mexico

    Ramsés E. Ramírez

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  1. Lisset Noriega
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  2. Alfonso Díaz
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  3. Daniel Limón
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Correspondence to Jose Manuel Perez-Aguilar or Francisco J. Melendez.

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This paper belongs to Topical Collection QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)

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Noriega, L., Díaz, A., Limón, D. et al. Inhibitory mechanism of 17β-aminoestrogens in the formation of Aβ aggregates. J Mol Model 25, 229 (2019). https://doi.org/10.1007/s00894-019-4128-y

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