Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach
Metadata
Show full item recordEditorial
MDPI
Materia
Alzheimer’s disease ADME Molecular docking and molecular dynamics
Date
2023-01-19Referencia bibliográfica
Silva, L.B... [et al.]. Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach. Molecules 2023, 28, 1035. [https://doi.org/10.3390/molecules28031035]
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PROPESP/UFPAAbstract
Acetylcholinesterase (AChE) enzymes play an essential role in the development ofAlzheimer’s
disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and
neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE)
enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID
4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein
and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT)
with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters
in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried
out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking,
molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot
spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and
ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by
Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and
Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic
routes and prediction of synthetic accessibility for the most promising compounds are also proposed.
In conclusion, this study shows that in silico modeling can be used to create new drug candidate
inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are
particularly promising for oral administration because they have a favorable drug-likeness profile,
excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.