β-Secretase-1: In Silico Drug Reposition for Alzheimer's Disease

Abstract

The β-secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer's disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer's with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer's disease, especially those targeting BACE-1.

Keywords: ADME; Alzheimer’s disease; in silico drug reposition; molecular docking; β-secretase 1.

Figure 1

Drugs associated with molecular targets related to Alzheimer’s.

Figure 2

(A) 3D overlay of Verubecestat (green) and EJ7 (pink) at the BACE-1 catalytic site. 2D interaction at the catalytic site of BACE-1 (B) Verubecestat, (C) EJ7.

Figure 3

ATC classification and routes of administration of drugs with better BCE than EJ7.

Figure 4

BACE-1 interaction with (A) 5 reposition candidates and reference inhibitors in 3D, 2D interaction at the catalytic site of BACE—(B) Fluphenazine, (C) Naratripan, (D) Bazedoxifene, (E) Frovatriptan, and (F) Raloxifene.