title: New small-size peptides modulators of the exosite of BACE1 obtained from a structure-based design.
abstract: We report here two new small-size peptides acting as modulators of the β-site APP cleaving enzyme 1 (BACE1) exosite. Ac-YPYFDPL-NH2 and Ac-YPYDIPL-NH2 displayed a moderate but significant inhibitory effect on BACE1. These peptides were obtained from a molecular modeling study. By combining MD simulations with ab initio and DFT calculations, a simple and generally applicable procedure to evaluate the binding energies of small-size peptides interacting with the exosite of the BACE1 is reported here. The structural aspects obtained for the different complexes were analyzed providing a clear picture about the binding interactions of these peptides. These interactions have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules using a reduced model. Although the approach used here was traditionally applied to the study of noncovalent interactions in small molecules complexes in gas phase, we show, through in this work, that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event of peptides modulators at the exosite of BACE1.
authors.affiliation: a Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Químicam, Facultad de Ciencias Exactas y Naturales y Agrimensura , Universidad Nacional del Nordeste , Av. Libertad 5470, Corrientes 3400 , Argentina.
authors.forename: Lucas J
authors.initials: LJ
authors.lastname: Gutierrez
authors.affiliation: a Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Químicam, Facultad de Ciencias Exactas y Naturales y Agrimensura , Universidad Nacional del Nordeste , Av. Libertad 5470, Corrientes 3400 , Argentina.|b Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL, CONICET) , Ejercito de Los Andes 950, 5700 San Luis , Argentina.
authors.forename: Emilio
authors.initials: E
authors.lastname: Angelina
authors.affiliation: c Department of Medical Chemistry , University of Szeged , H-6720 Szeged , Dóm tér 8., Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gyebrovszki
authors.affiliation: c Department of Medical Chemistry , University of Szeged , H-6720 Szeged , Dóm tér 8., Hungary.
authors.forename: Lívia
authors.initials: L
authors.lastname: Fülöp
authors.affiliation: a Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Químicam, Facultad de Ciencias Exactas y Naturales y Agrimensura , Universidad Nacional del Nordeste , Av. Libertad 5470, Corrientes 3400 , Argentina.
authors.forename: Nelida
authors.initials: N
authors.lastname: Peruchena
authors.affiliation: d Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis , Chacabuco 917, 5700 San Luis , Argentina.|e Instituto de Matemática Aplicada San Luis (IMASL,CONICET) , Italia 1556, 5700 San Luis , Argentina.
authors.forename: Héctor A
authors.initials: HA
authors.lastname: Baldoni
authors.affiliation: c Department of Medical Chemistry , University of Szeged , H-6720 Szeged , Dóm tér 8., Hungary.
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.affiliation: b Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL, CONICET) , Ejercito de Los Andes 950, 5700 San Luis , Argentina.|d Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis , Chacabuco 917, 5700 San Luis , Argentina.
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Enriz
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D021281:Quantitative Structure-Activity Relationship
chemical_list: D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; exosite-modulators; molecular modeling; molecular simulations; β-secretase