Drug Discovery to Drug Development of BACE1 Inhibitor as Antialzheimer’s: A Review

Abstract

Alzheimer’s Disease (AD) is a complex and progressive neurodegenerative disease, and the most common cause of dementia usually occurs due to old age. Production and accumulation of amyloid-β peptide (Aβ) represent the major pathological event of the disease. The formation of amyloid-β results due to proteolytic cleavage of amyloid precursor protein (APP) by beta-site amyloid precursor protein cleaving enzyme (BACE1) shown as the amyloid hypothesis, a prevalent theory for AD pathogenesis. Thus, BACE1 represents a novel target to decrease cerebral Aβ concentration and slow down the disease’s progression. The structure-based drug design approach led to a wide variety of small molecules with the mechanism of action centered around inhibition of β-secretase protease (BACE1), which are shown to have drug-like properties and reduce brain Aβ levels. Based on transition state isosteres, BACE1 inhibitors can largely be classified as peptidomimetics and non-peptidomimetics. The subclasses of the two categories have been covered with different scaffolds like statin, norstatin, carbinamine, hydroxyethylene, hydroxyethylamine, acyl guanidine, 2-aminopyridine, aminoimidazole, aminohydantoin, aminothiazoline, aminooxazoline, aminoquinoline, piperazine-based. Among these small molecules, those who fulfilled general requirements for a drug aimed at the central nervous system (CNS) and selectivity over other aspartyl proteases reached the final pipeline of clinical trials. Here, in this review, we summarize the journey of BACE1 inhibitors through different practices of drug design development, Structural Activity Relationship (SAR), and other inhibitor candidates that are currently in clinical trials as BACE1 inhibitors.

Unveiling the Brazilian Kefir Microbiome: Discovery of a novel Lactobacillus kefiranofaciens (LkefirU) genome and in silico prospection of bioactive peptides with potential anti-Alzheimer properties

“…These amino acid residues are in the FLAP region, and this interaction could reults in BACE inhibition. Moreover, the VPGYPFLPI interacts with residue Asn233, similar to a BACE1 inhibitor called hydroxyethylamine [47].…”

Ligand Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamic simulation and In-silico ADMET Studies for the Discovery of Potential BACE-1 Inhibitors

“…The extracellular portion of BACE-1 contains the active amino acid residues Asp 32 and Asp 228. Several molecular docking analyses have revealed the interaction of these catalytic aspartates with a wide range of BACE-1 inhibitors [21][22][23]. The 3D crystal structure of BACE-1 PDB ID: 7MYI and its docked inhibitor are shown in Fig.…”

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

“…β-secretase-1 (BACE-1) is a type of membrane-bound aspartic protease, which is 501 amino acids in length (five key domains, a signal peptide, and pro-catalytic, catalytic, transmembrane, and cytoplasmic domains have been identified in the enzyme) [23]. Its crystalline structure reveals that the proteolytic pocket is relatively large, being able to accommodate up to 11 amino acid residues [23,24]. Amyloid plaques, composed mainly of β-amyloid peptide, are progressively formed in the brain of Alzheimer's patients, and mutations in three genes cause the early onset of Familial Alzheimer's disease (FAD) by directly increasing the toxic peptide that promotes β-amyloid 42 [25][26][27].…”