RESUMO
Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood-brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.
Assuntos
Inibidores da Colinesterase/análise , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Interface Usuário-Computador , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Galantamina/química , Galantamina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neurotoxinas/toxicidade , Bibliotecas de Moléculas PequenasRESUMO
Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer's disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aß) oligomers and inhibits the formation of Aß plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.