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dc.contributor.author
Richmond, Victoria
dc.contributor.author
Falcone, Bruno Nicolas
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Maier, Marta Silvia
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Arroyo Máñez, Pau
dc.date.available
2024-02-27T12:24:50Z
dc.date.issued
2023-07
dc.identifier.citation
Richmond, Victoria; Falcone, Bruno Nicolas; Maier, Marta Silvia; Arroyo Máñez, Pau; Putting the Puzzle Together To Get the Whole Picture: Molecular Basis of the Affinity of Two Steroid Derivatives to Acetylcholinesterase; American Chemical Society; ACS Omega; 8; 28; 7-2023; 25610-25622
dc.identifier.issn
2470-1343
dc.identifier.uri
http://hdl.handle.net/11336/228544
dc.description.abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has no cure because its etiology is still unknown, and its main treatment is the administration of acetylcholinesterase (AChE) inhibitors. The study of the mechanism of action of this family of compounds is critical for the design of new more potent and specific inhibitors. In this work, we study the molecular basis of an uncompetitive inhibitor (compound 1, 2β, 3α-dihydroxy-5α-cholestan-6-one disulfate), which we have proved to be a peripheral anionic site (PAS)-binding AChE inhibitor. The pipeline designed in this work is key to the development of other PAS inhibitors that not only inhibit the esterase action of the enzyme but could also modulate the non-cholinergic functions of AChE linked to the process of amylogenesis. Our studies showed that 1 inhibits the enzyme not simply by blocking the main gate but by an allosteric mechanism. A detailed and careful analysis of the ligand binding position and the protein dynamics, particularly regarding their secondary gates and active site, was necessary to conclude this. The same analysis was executed with an inactive analogue (compound 2, 2β, 3α-dihydroxy-5α-cholestan-6-one). Our first computational results showed no differences in affinity to AChE between both steroids, making further analysis necessary. This work highlights the variables to be considered and develops a refined methodology, for the successful design of new potent dual-action drugs for AD, particularly PAS inhibitors, an attractive strategy to combat AD.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
STEROIDS
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MOLECULAR MODELLING
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ACETYLCHOLINESTERASE
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ALZHEIMER'S DISEASE
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Química Orgánica
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Ciencias Químicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Putting the Puzzle Together To Get the Whole Picture: Molecular Basis of the Affinity of Two Steroid Derivatives to Acetylcholinesterase
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-02-26T15:59:48Z
dc.journal.volume
8
dc.journal.number
28
dc.journal.pagination
25610-25622
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil
Fil: Falcone, Bruno Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil
Fil: Maier, Marta Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil
Fil: Arroyo Máñez, Pau. Universidad Politécnica de Valencia; España
dc.journal.title
ACS Omega
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1021/acsomega.3c03749
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