New mimetic peptides inhibitors of Aβ aggregation: Molecular guidance for rational drug design
| Autor: | Sebastian A. Andujar, Kerensa Broersen, Ana M. Rodríguez, Carina M. L. Delpiccolo, Ellen Hubin, Luciana Méndez, Exequiel Ernesto Barrera Guisasola, Ivonne M. Kraan, Ricardo D. Enriz, Marcelo F. Masman |
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| Přispěvatelé: | Nanobiophysics, Molecular Dynamics |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular LINEAR CONSTRAINT SOLVER PARTICLE MESH EWALD Protein Conformation Amyloid β-protein BETA-RPOTEIN MIMETIC Aggregation modulating effect chemistry.chemical_compound Molecular dynamics MOLECULAR THERAPEUTIC STRATEGY Drug Discovery Cognitive decline Amyloid beta-protein SHEET BREAKER PEPTIDES PROTEIN MISFOLDING DISEASES Ciencias Químicas MODELLING PEPTIDES General Medicine SOLID-STATE NMR ALZHEIMERS-DISEASE Thioflavin Molecular modelling Hydrophobic and Hydrophilic Interactions CIENCIAS NATURALES Y EXACTAS Amyloid Drug design Molecular Dynamics Simulation Hydrophobic effect Mimetic peptides AMYLOID Alzheimer Disease Humans Molecule Pharmacology RAT PRIMARY NEURONS Amyloid beta-Peptides DYNAMICS SIMULATIONS Molecular dynamics simulations Otras Ciencias Químicas Organic Chemistry Water Peptide Fragments Crystallography chemistry Drug Design SOLUBLE AMYLOID OLIGOMERS 2023 OA procedure Biophysics Peptidomimetics Salt bridge |
| Zdroj: | European journal of medicinal chemistry, 95, 136-152. Elsevier European Journal of Medicinal Chemistry, 95, 136-152. ELSEVIER MASSON, CORPORATION OFFICE |
| ISSN: | 0223-5234 |
| Popis: | 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. Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Hubin, Ellen. University of Twente; Países Bajos. Vrije Universiteit Brussel; Bélgica Fil: Broersen, Kerensa. University of Twente; Países Bajos Fil: Kraan, Ivonne M.. University of Twente; Países Bajos Fil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Masman, Marcelo Fabricio. University Of Groningen; Países Bajos Fil: Rodríguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina |
| Databáze: | OpenAIRE |
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