Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.
Acetylcholinesterase
Alzheimer
DFT
Huperzine A
Iron complex
Molecular docking
Molecular modeling
Zinc complex
Journal
Journal of molecular modeling
ISSN: 0948-5023
Titre abrégé: J Mol Model
Pays: Germany
ID NLM: 9806569
Informations de publication
Date de publication:
08 Jun 2024
08 Jun 2024
Historique:
received:
16
02
2024
accepted:
21
05
2024
medline:
8
6
2024
pubmed:
8
6
2024
entrez:
8
6
2024
Statut:
epublish
Résumé
Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔG Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.
Identifiants
pubmed: 38850372
doi: 10.1007/s00894-024-05991-4
pii: 10.1007/s00894-024-05991-4
doi:
Substances chimiques
huperzine A
0111871I23
Alkaloids
0
Sesquiterpenes
0
Cholinesterase Inhibitors
0
Acetylcholinesterase
EC 3.1.1.7
Zinc
J41CSQ7QDS
Iron
E1UOL152H7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
200Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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