In silico Identification of Novel Potential BACE-1 Inhibitors for Alzheimer’s Disease Treatment: Molecular Docking, Pharmacophore Modeling and Activity and Synthetic Accessibility Predictions

Aims: Alzheimer's Disease (AD) is a progressive neurodegenerative disease accompanied by loss of memory and cognition. With its causes still unknown, one of the main hypotheses related to its pathogenesis is the amyloidal, where the abnormal metabolism of amyloid precursor protein (APP), in this case cleaved by β-secretase enzyme (BACE-1), generates sAPPβ, subsequent action of β-secretase generates β-amyloid. This gives the β-secretase importance as a therapeutic target of AD, since their inhibition can control the onset and progression of the disease. This work intends to propose three new compounds with inhibitory activity for BACE-1 that may be potential drug candidates for AD treatment.
Place and Duration of Study: Laboratory of Modeling and Computational Chemistry (LMCC) at Federal University of Amapá (UNIFAP), Macapá, Brazil, between January 2014 and February 2015.
Methodology: First, we selected a group of inhibitors deposited in the BindingDB database as well as a crystallographic protein solved in the Protein Data Bank (PDB). Then we performed a prediction of ligand binding sites of BACE-1. To propose the binding mode of the inhibitor with the enzyme, molecular docking and molecular interactions analyses were performed. New proposals with potential inhibitory activity of BACE-1 in addition to a pharmacophore perception calculation as well as biological activity and synthetic accessibility predictions were made.
Results: A group of 40 inhibitors was selected from the database BindingDB, which were submitted to molecular docking simulation (for verification of the possible binding modes with the biological target), when analyzing the results of molecular docking, the hydrogen bond proved dominant over the others (approximately 74%). For pharmacophore perception calculation, the following characteristics were observed: a hydrophobic group, three aromatic groups, three donors and seven hydrogen bond acceptors. The target protein had its regions of the binding site predicted, and the most likely ligand binding site agree with the one already reported in the literature as the catalytic region of BACE-1. This allowed us to model three proposals that, in turn, had their predicted biological activities for BACE-1 as well as their synthetic accessibility.
Conclusion: Results showed that the proposals are promising BACE-1 inhibitors, with suitable drug-like properties, for future AD tretament.