Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach
Metadatos
Mostrar el registro completo del ítemAutor
Barbosa, Deyse B.; do Bomfim, Mayra R.; de Oliveira, Tiago A.; da Silva, Alisson M.; Taranto, Alex G.; Cruz, Jorddy N.; de Carvalho, Paulo B.; Campos Rosa, Joaquín María; Rodrigues dos Santos, Cleydson Breno; Leite, Franco H. A.Editorial
MDPI
Materia
Alzheimer’s disease Molecular docking Molecular dynamics
Fecha
2023-11-28Referencia bibliográfica
Barbosa, D.B.; do Bomfim, M.R.; de Oliveira, T.A.; da Silva, A.M.; Taranto, A.G.; Cruz, J.N.; de Carvalho, P.B.; Campos, J.M.; Santos, C.B.R.; Leite, F.H.A. Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach. Pharmaceuticals 2023, 16, 1657. https://doi.org/10.3390/ph16121657
Patrocinador
PPBE and PPGCF/UEFS; Fundação de Amparo à Pesquisa do Estado de Minas Gerais—FAPEMIG, grants APQ-02741-17, APQ-00855-19, APQ-01733-21, and APQ-04559-22; Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq-Brazil, grants 305117/2017-3, 426261/2018-6; Fellowship of 2021 (grant 310108/2020-9)Resumen
Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia
in the world. The causes of this disease are not fully understood but seem to involve two essential
cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and
BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat
the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple
enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling
of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four
hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and
used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping
rates with the pharmacophore were subjected to molecular docking against the three enzymes and
those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological
parameters and commercial availability. The structure exhibiting the greatest inhibitory potential
against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the
stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733
can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays
are planned to validate those results.