Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.
Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.
Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F. Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F.
Maricarmen
M
Hernández-Rodríguez
Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F.
José
J
Correa-Basurto
Laboratorio de Investigación Departamento de Química Inorgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F.
Federico
F
Martínez-Ramos
Laboratorio de Investigación en Química Orgánica y Supramolecular, Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional. Av. Acueducto s/n Barrio la Laguna Ticomán, México, D.F.
Itzia Irene
II
Padilla-Martínez
Laboratorio de Investigación Bioquímica, Sección de Estudios de Posgrado e Investigación, ENMyH-Instituto Politécnico Nacional, La Escalera Ticoman, México, D.F.
Claudia G
CG
Benítez-Cardoza
Laboratorio de Cultivo Celular, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F.
Elvia
E
Mera-Jiménez
Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F.
Martha Cecilia
MC
Rosales-Hernández
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology; D055598:Chemical Phenomena; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D009842:Oligopeptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; C414614:OM99-2; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases
Acetylcholinesterase; Alzheimer's disease; amyloid-β; inhibitor; β-site AβPP cleaving enzyme 1