title: 2D QSAR studies on series of human beta-secretase (BACE-1) inhibitors.
abstract: β-secretase (BACE-1) plays a pivotal role in the β-Amyloid plaques formation, which is responsible for progressive cognitive and memory loss commonly found in Alzheimer disease patients. As a consequence, it has been considered as a good target for drug development efforts. Early work focused on the synthesis of peptidomimetics, but poor pharmacokinetics profile prevented advancing lead compounds to clinical trials. As an alternative, aminoimidazoles, aminohydantoins and aminopyridines derivatives that inhibit BACE-1 were designed. Herein we report statistically sound descriptor- based (r(2) = 0.87, q(2) = 0.85, 6 PCs) and fragment-based (r(2) = 0.91, q(2) = 0.84, 6 PCs) QSAR models, that show high predictive ability (r(2)pred = 0.84, averaged r(2)m=0.78) and underscore polar interactions that are important for BACE-1 inhibition.
authors.forename: Daniela Santos
authors.initials: DS
authors.lastname: Cruz
authors.affiliation: Laboratorio de Bioinformatica e Modelagem Molecular, Faculdade de Farmacia, Universidade Federal da Bahia, CEP 40170-115, Brazil. castilho@ufba.br.
authors.forename: Marcelo Santos
authors.initials: MS
authors.lastname: Castilho
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D006827:Hydantoins; D007093:Imidazoles; C014973:2-aminoimidazole; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human