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. 2022 Jan 28;27(3):918.
doi: 10.3390/molecules27030918.

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer's Disease

Affiliations

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer's Disease

Luis Daniel Goyzueta-Mamani et al. Molecules. .

Abstract

Background: Despite research on the molecular bases of Alzheimer's disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers.

Methods: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials.

Results: Our results demonstrated the increased bioactivity of three plants' metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau.

Conclusions: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.

Keywords: Alzheimer’s disease; Peru; Peruvian native plants; brassicasterol; floribundic acid; in silico; polypharmacology; rutin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Binding affinities of molecules screened from Smallanthus sonchifolius, Lepidium meyenii, Croton lechieri, Uncaria tomentosa, Physialis perivianus, and Minthostachys mollis against: (A) tau peptide, (B) amyloid beta (1–40), and (C) AT1R. NS: not significant. * p < 0.05 and ** p < 0.0.1 significance among groups. Box plots with minimum and maximum values of binding affinities. Scatter plot showing binding affinity versus drug-likeness score for: (D) tau, (E) amyloid beta (1–40), and (F) AT1R.
Figure 2
Figure 2
Representation of DM trajectories over 100 ns for AT1R, amyloid beta, and tau. The figures on the right side are the RMSD plots, and those on the left side are the RMSF plots of the backbone per residue. (A) The tendency of the RMSD plot for the AT1R–rutin system shows that the protein does not constantly deviate from its original conformation even though this compound generates the largest fluctuations in AT1R (RMSF analysis); (B) the RMSD plot for amyloid beta in its native state (black line) shows a high structural instability due to the size and lack of other secondary conformations. However, the coupled systems reduce this deviation; (C) tau with ligands shows a tendency of high conformational stability.
Figure 3
Figure 3
MD simulation and docking analysis shows the formation of hydrogen bond interactions between the AT1R and: (A) floribundic acid, (B) glucobrassicin, (C) telmisartan, and (D) rutin.
Figure 4
Figure 4
MD simulation and docking analysis shows the formation of hydrogen bond interactions between the amyloid beta and: (A) brassicasterol, (B) grapeseed extract, (C) kaurenoic acid, and (D) rutin binding interactions between the ligand and receptor.
Figure 5
Figure 5
MD simulation and docking analysis shows the formation of hydrogen bond interactions between the tau protein and: (A) nicotinamide, (B) rutin, (C) brassicasterol, and (D) floribundic acid binding interactions between the ligand and receptor.
Figure 6
Figure 6
Diagram illustrating the polypharmacological activity of the metabolites rutin, brassicasterol, and floribundic acid on tau, amyloid beta, and AT1R, AD pathologic markers.

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