In silico evaluation of ginsenoside analogs as β and γ-secretase inhibitors in Alzheimer’s disease

Context: Alzheimer's disease is rising significantly and could reach alarming numbers in the coming decades. Therefore, diverse pathways are being explored to discover new therapies. Ginsenosides could reduce cellular damage, protect brain neurons, and cognitive function. Due to a lack of clarity regarding the potential inhibitory mechanisms of these compounds on pathophysiological pathways in β-amyloid development, bioinformatic analysis has been employed. Aims: To evaluate, through in silico analysis, analogs of ginsenosides as potential β- and γ-secretase inhibitors for Alzheimer's disease treatment. Methods: Ginsenoside analogs (798) were selected from the PubChem database and minimized using Open Babel Tools. β-secretase and γ-secretase were chosen from the Protein Data Bank database and prepared using AutoDockTools 1.5.7. Molecular docking for analogs and their co-crystallized molecules was executed using AutoDock-Vina. The interactions and binding types of complexes were analyzed. Molecular dynamics simulations were performed for analogs 146521791, 134688678, and Ginsenoside Rg1, as well as their co-crystallized molecules, using AMBER20 software. Results: In molecular docking, the molecules demonstrated superior binding affinity toward the β-secretase active site, with a score of 146521791, and for γ-secretase, it was 134688678. In molecular dynamics simulation, all β-secretase complexes showed structural stability (RMSD <2.5 Å), with high flexibility in residue position between 150-175, 312-325, and 362-375 (RMSF of 2-3 Å); for γ-secretase, the native protein shows less RMSD value variation in comparison to the other complexes, also all analog complexes showed the same movement variation in the γ-secretase residues with values between 1 and 3 Å. Conclusions: This suggests its therapeutic potential as an alternative Alzheimer's disease therapy, highlighting its ability to interfere with key enzymatic processes involved in the formation of amyloid peptide. This reveals its therapeutic potential as an alternative Alzheimer's disease therapy and highlights its ability to interfere with key enzymatic processes in the formation of amyloid peptides.