Molecular dynamics and structure-based virtual screening and identification of natural compounds as Wnt signaling modulators: possible therapeutics for Alzheimer’s disease

Abstract

Wnt signaling pathway is an evolutionarily conserved pathway responsible for neurogenesis, axon outgrowth, neuronal polarity, synapse formation, and maintenance. Downregulation of Wnt signaling has been found in patients with Alzheimer’s disease (AD). Several experimental approaches to activate Wnt signaling pathway have proven to be beneficial in alleviating AD, which is one of the new therapeutic approaches for AD. The current study focuses on the computational structure-based virtual screening followed by the identification of potential phytomolecules targeting different markers of Wnt signaling like WIF1, DKK1, LRP6, GSK-3β, and acetylcholine esterase. Initially, screening of 1924 compounds from the plant-based library of Zinc database was done for the selected five proteins using docking approach followed by MM-GBSA calculations. The top five hit molecules were identified for each protein. Based on docking score, and binding interactions, the top two hit molecules for each protein were selected as promising molecules for the molecular dynamic (MD) simulation study with the five proteins. Therefore, from this in silico based study, we report that Mangiferin could be a potential molecule targeting Wnt signaling pathway modulating the LRP6 activity, Baicalin for AChE activity, Chebulic acid for DKK1, ZINC103539689 for WIF1, and Morin for GSk-3β protein. However, further validation of the activity is warranted based on in vivo and in vitro experiments for better understanding and strong claim. This study provides an in silico approach for the identification of modulators of the Wnt signaling pathway as a new therapeutic approach for AD. Graphical Abstract

Exploring the Novel Anticonvulsant Phytochemicals from Glycyrrhiza glabra: An In Silico Approach

“…The variation of RMSD describes the stability of the complex over time. The acceptable range of RMSD values for the protein‐ligand interactions is 0.1–0.3 nm [65] . Except Glabrene complex, there is a slight fluctuation in the RMSD of all the complexes until 4 ns, after which their stability is maintained until 40 ns, displayed in Figure 4a.…”

“…The human GABA‐A receptor α1‐β2‐γ2 subtype protein (6X3X, resolution 2.92 Å) was retrieved from the RCSB Protein Data Bank (PDB) [6,65] . All ligands were detached from the protein using UCSF chimera‐v 1.16.…”

“…The acceptable range of RMSD values for the protein-ligand interactions is 0.1-0.3 nm. [65] Except Glabrene complex, there is a slight fluctuation in the RMSD of all the complexes until 4 ns, after which their stability is maintained until 40 ns, displayed in Figure 4a. Glabrene RMSD value slightly changed after 20 ns and remained unchanged throughout the simulation.…”

“…The human GABA-A receptor α1-β2-γ2 subtype protein (6X3X, resolution 2.92 Å) was retrieved from the RCSB Protein Data Bank (PDB). [6,65] All ligands were detached from the protein using UCSF chimera-v 1.16. AutoDock tool 1.5.7 was used to remove the water molecules, adding hydrogen atoms and Kollman charges for the preparation of protein.…”

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

“…The complexes showed comparable stability to the unbound protein and protein–22,26-azasterol complex. The unbound Ld SMT and the protein–ligand complexes experienced a high volatility within the first 10 ns of the MD simulation with an RMSD fluctuation of 0.15 nm ( Supplementary Figure S2a ), which is classified as acceptable, since the drifting falls within the range 0.1–0.3 ns [ 101 ]. Equilibration was therefore reached afterward with a low RMSD fluctuation of ≤0.05nm.…”