title: Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of Aβ1-42.
abstract: 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 Aβ1-42 pathological aggregation represents a field of research interest. Several Aβ1-42 fibrillization 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 Aβ1-42 in 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 Aβ1-42 in 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 Aβ1-42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.
authors.affiliation: Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Delegación Miguel Hidalgo, México D.F., México; Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Delegación Miguel Hidalgo, México D.F., México.
authors.forename: Maricarmen
authors.initials: M
authors.lastname: Hernández-Rodríguez
authors.affiliation: Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Delegación Miguel Hidalgo, México D.F., México.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Quimica inorgánica-orgánica del Departamento de Ciencias Químicas, de la Facultad de Estudios Superiores Cuautitlán Campo 1, Universidad Nacional Autónoma de México, Avenida 1o de Mayo S/N, Santa María las Torres, Cuautitlán Izcalli, Estado de México, México.
authors.forename: María Inés
authors.initials: MI
authors.lastname: Nicolás-Vázquez
authors.affiliation: Quimica inorgánica-orgánica del Departamento de Ciencias Químicas, de la Facultad de Estudios Superiores Cuautitlán Campo 1, Universidad Nacional Autónoma de México, Avenida 1o de Mayo S/N, Santa María las Torres, Cuautitlán Izcalli, Estado de México, México.
authors.forename: René
authors.initials: R
authors.lastname: Miranda-Ruvalcaba
authors.affiliation: Laboratorio de Investigación Bioquímica, Sección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Guillermo Massieu H 239, Gustavo A. Madero, La Escalera, México D.F., México.
authors.forename: Claudia Guadalupe
authors.initials: CG
authors.lastname: Benítez-Cardoza
authors.affiliation: Laboratorio de Investigación en Inmunología., Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Delegación Miguel Hidalgo, México D.F., México.
authors.forename: Aldo Arturo
authors.initials: AA
authors.lastname: Reséndiz-Albor
authors.affiliation: Centro de Nanociencias y Micro y Nanotecnología, Instituto Politécnico Nacional, Luis Enrique Erro S/N, U. Prof Adolfo López Mateos, Gustavo A. Madero, México D.F., México.
authors.forename: Juan Vicente
authors.initials: JV
authors.lastname: Méndez-Méndez
authors.affiliation: Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Delegación Miguel Hidalgo, México D.F., México.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Rosales-Hernández
mesh_terms: D000588:Amines / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000588:Amines; D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; D054852:Small Molecule Libraries; C075222:amyloid beta-protein (1-42)