title: Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations.
abstract: Inhibition of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity, which has different volume and shape compared to BACE2 and CTSD. Hindrance effects avoid the accommodation of ligands in the small catalytic site of BACE2, resulting in a lower affinity and the high cavity of CTSD results in the formation of a small number of interactions with the ligands, although they show a similar binding mode with BACE1. These results might help to rationalize the design of selective BACE1 inhibitors.
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática y diseño de farmaos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico; Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico; Departamento de Farmacología, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico.
authors.forename: Maricarmen
authors.initials: M
authors.lastname: Hernández-Rodríguez
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática y diseño de farmaos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico; Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico. Electronic address: corrjose@gmail.com.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos, 29071 Málaga, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutiérrez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain; Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática y diseño de farmaos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico; Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México D.F, Mexico. Electronic address: marcrh2002@yahoo.com.mx.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Rosales-Hernández
mesh_terms: D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D011480:Protease Inhibitors; D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases
keywords: Alzheimer; Beta secretases; Docking molecular dynamics simulations; Molecular modeling