title: In Silico Design of Beta-Secretase Inhibitors in Alzheimer's Disease.
abstract: Alzheimer's disease is the major cause of senile dementia, flewing out 10% of 65 years old and 50% of 85 years old global population. The major fisiopathologic characteristics of Alzheimer's disease are the deposition of extracellular neuritic plaques and the presence of intracellular neurofibrillary tangles in memory-related areas of the brain. The plaques are composed by the β-amyloid peptide with 40 or 42 residues, result from hydrolysis of the amyloid precursor protein by the β-secretase 1 (BACE-1) on the amyloidogenic pathway, that begins with the BACE-1 and which inhibition is considered one of the most promising treatments available of Alzheimer's disease. In this work, molecular modeling techniques such as virtual screening of compound libraries, pharmacophore-based virtual screening, molecular interaction fields, ADME/Tox predictions, and similarity search were used to design novel inhibitors of BACE-1, starting from structures available in the Protein Data Bank. The results obtained from all virtual screening techniques leaded to 10 promising compounds, which were then evaluated by enzymatic assays, and, three of them showed inhibitory activity of BACE-1 at a 1 μm range.
authors.affiliation: Faculdade de Medicina de Ribeirão Preto, USP, Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, 14049-900, Brazil.
authors.forename: Evandro Pizeta
authors.initials: EP
authors.lastname: Semighini
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005470:Fluorometry / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer; BACE-1; drug design; inhibition; molecular modeling