In silico study of ginsenoside analogues as possible BACE1 inhibitors involved in Alzheimer's disease

Abstract

Background: Neurodegenerative disorders such as Alzheimer's disease show an alarming prevalence in the population, with around 50 million affected individuals worldwide, and is associated with the development of dementia, mainly affecting the elderly population. Currently, the treatments used are based on slowing the progression of the clinical symptoms of Alzheimer’s; however, no specific treatment has been found that induces reversion of the disease. Natural products may induce a wide range of palliative effects, such as ginseng (Panax ginseng), which produces secondary metabolites called ginsenosides, which have multiple therapeutic applications, including for neurodegenerative diseases such as Alzheimer’s. Methods: A virtual screening was carried out, using the CHEMBL database to find analogs of ginsenosides based on the ginsenoside Rg1 (CHEMBL501637). Next, the molecules were optimized and their format modified. The structure of BACE1 was downloaded from the Protein Data Bank database (ID: 1FKN) and prepared for the development of molecular docking using the PyRx software. A database of the ligands was created and molecular docking experiments were carried out, obtaining affinity energy values ​​in Kcal/mol. Results: Of the 27 analogues studied, it was found that the molecules CHEMBL451292, CHEMBL510371 and CHEMBL503302 showed considerable affinity with BACE1 when compared with the reference molecules (verubecestat and donepezil). These affinity energy values for CHEMBL451292, CHEMBL510371 and CHEMBL503302 ​​were -9.6, -8.1 and -7.6 Kcal/mol, respectively. Likewise, the binding site of the ligands to BACE1 were identified, with the main interactions being van der Waals and hydrogen bonding. Conclusions: Three ginsenoside analogues showed a similar binding energy with BACE1 compared to the reference drugs. The residues involved in the inhibitory activity of BACE1 and the type of predominant interactions were identified, which agreed with previous reports.