RT Journal Article
T1 Computer-Aided Structure-Based Design of Multitarget Leads for Alzheimer’s Disease
A1 Domínguez, José L.
A1 Fernández-Nieto, Fernando
A1 Castro Pérez, María de los Ángeles
A1 Catto, Marco
A1 Paleo Pillado, María Rita
A1 Porto, Silvia
A1 Sardina López, Francisco Javier
A1 Brea Floriani, José Manuel
A1 Carotti, Angelo
A1 Villaverde Cameron-Walker, María del Carmen
A1 Sussman, Fredy Salomon
AB 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
PB American Chemical Society
SN 1549-9596
YR 2015
FD 2015
LK http://hdl.handle.net/10347/16986
UL http://hdl.handle.net/10347/16986
LA eng
NO Domínguez, J., Fernández-Nieto, F., Castro, M., Catto, M., Paleo, M., & Porto, S. et al. (2015). Computer-Aided Structure-Based Design of Multitarget Leads for Alzheimer’s Disease. J. Chem. Inf. Model., 55(1), 135-148. doi: 10.1021/ci500555g
NO Financial support from the Ministerio de Economia yCompetitividad of Spain (Project CTQ2011-22436) and theXunta de Galicia (CN2011/047 and 10CSA209063PR) isgratefully acknowledged
DS Minerva
RD 24 abr 2026