title: Computer-aided structure-based design of multitarget leads for Alzheimer's disease.
abstract: Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Domínguez
authors.forename: Fernando
authors.initials: F
authors.lastname: Fernández-Nieto
authors.forename: Marian
authors.initials: M
authors.lastname: Castro
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: M Rita
authors.initials: MR
authors.lastname: Paleo
authors.forename: Silvia
authors.initials: S
authors.lastname: Porto
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Sardina
authors.forename: José M
authors.initials: JM
authors.lastname: Brea
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Villaverde
authors.forename: Fredy
authors.initials: F
authors.lastname: Sussman
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002227:Carbazoles; D007211:Indoles; D008024:Ligands; D010446:Peptide Fragments; C092395:amyloid beta-protein (12-28); C041514:carbazole; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human