A Novel Inhibitor of DKK1/LRP6 Interactions Against the Alzheimer Disease: An Insilco Approach

Abstract

The activation of the Wnt signaling pathway is implicated in a neuroprotective mechanism against the Alzheimer disease. When this pathway is blocked, it activates GSK3 beta, leading to tau hyperphosphorylation and the apoptosis of neurons. Dickkopf-related protein 1 (DKK1) is a protein that competes with the Wnt ligand for the low-density lipoprotein receptor–related protein 6 (LRP6) receptor’s binding, interrupting the Wnt-induced Fzd-Wnt-LRP6 complex. This counteracts Wnt’s neuroprotective effect and contributes to the progression of the Alzheimer disease. The aim of this study was to use in silico approach to develop new agents that can combat the Alzheimer disease by targeting the interaction between DKK1 and LRP6. To achieve this, we conducted a virtual screening (Vsw) of the Asinex-CNS database library (n = 54 513) compounds against a generated grid in LRP6 protein. From this screening, we selected 6 compounds based on their docking score and performed molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations on the selected ligands. Next, we evaluated the Absorption, Distribution, Metabolism, and Excretion (ADME) results of the 6 screened compounds using the Quick prop module of Schrödinger. We then employed several computational techniques, including PCA (Principal Component Analysis), DCCM (Dynamic Cross-Correlation Map), molecular dynamics simulation, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)–based negative binding free energy (BFE) calculation, to further analyze the compounds. Our extensive computational analysis resulted in the identification of 3 potential hits, LAS 29757582, LAS 29984441, and LAS 29757942. These compounds were found to block the interaction of DKK1 with LRP6 (A and B interface) protein, and their potential as therapeutic agents was supported by negative BFE calculation. Therefore, these compounds show potential as possible therapeutic agents for treating the Alzheimer disease through targeting the interaction between DKK1 and LRP6.

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

“…The solvation free energy (G sol ) is divided into polar (E PB ) and nonpolar (E SA ) components, in which the polar solvation energy was calculated using the Poisson–Boltzmann equation, and the nonpolar solvation energy was computed based on the solvent-accessible surface area (SASA), with γ set to the default value [ 74 ]. The configuration entropy (TΔS) was attributed to the contributions of entropy temperature and S entropy [ 75 ].…”

“…The PCA method utilizes the covariance matrix to extract the most important functional motions from the protein dynamics coordinates. The covariance matrix includes the atomic fluctuations of each residue’s C-alpha and provides the orthogonal eigenvectors and their corresponding eigenvalues [ 75 ]. The eigenvalues represent the amplitudes of the motions, while eigenvectors describe the directions of the motions, which are then used to calculate principal components (PCs).…”

“…The parentheses show the average of all structures sampled on the MD trajectory. The dynamic cross-correlation matrix (DCCM) was used to identify the cross-correlation shifts of the backbone atoms and to show protein backbone conformation shifts, and was performed using RStudio software (version 4.3.1) and the Bio3d application [ 75 , 76 , 77 ]. The cross-correlation coefficient value fluctuated from −1 to 1, and the resulting dynamic cross-correlation matrices displayed amino acids that have both positive and negative effects.…”