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

Abstract

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 βsecretase generates β-amyloid. This gives the β-secretase importance as a therapeutic target of

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…As described above in the introduction, the GSK‐3β pathological hypothesis has had a significant impact on research for the treatment of AD. In fact, there is now no doubt that potential GSK‐3β‐selective inhibitors, which modulate this enzyme′s activity and consequently prevent the formation of neurofibrillary tangles by hyperphosphorylated tau protein as well as decreased Aβ overproduction, may represent an effective therapeutic approach for the treatment of AD …”

“…[109,110,111] Compounds 9 and 10 enhancet he affinity of acetylcholine for the orthosteric site of M1, whereas 11 was found to be effective at reversing learning impairment in am ousem odel of AD. [109] Other compounds described as M1 PAMs are PQCA (18)a nd MK-7622 ( 19) ( Figure 2), where the former exhibited good results in in vivos tudies including increased learning and memory in at ransgenic (Tg2576)A D mousem odel, [112] and in which the latter was found to be a highly selectiveM 1P AM in phase II studies with AD patients. [113] Other relevant and noteworthy M1 PAMs illustrate the structural diversity of this compound class.…”

“…In fact, there is now no doubt that potentialG SK-3b-selective inhibitors, which modulate this enzyme'sa ctivity and consequently preventt he formation of neurofibrillary tangles by hyperphosphorylated tau protein as well as decreased Ab overproduction,m ay represent an effective therapeutic approach for the treatment of AD. [19][20][21]189] Besides the metal inhibitor Li + , [190] the most relevant inhibitors are classified according to the following modes of binding to GSK-3b:A TP-competitive inhibitors, non-ATP-competitive inhibitors, irreversible inhibitors, and allostericinhibitors. [187,191] ATP-competitive inhibitors for GSK-3b have been discovered from different sources, including marine organisms (e.g.,i ndirubin (42), Figure 5) and its analogues with IC 50 values in the range of 5-50 nm, [192,193] and hymenialdisine (43,F igure 5) with IC 50 = 10 nm.…”

“…Patients with AD may also have pathological patterns including increased β‐amyloid (Aβ) peptide concentration, with consequent deposition of amyloid plaques, as well as the appearance of neurofibrillary tangles that are made up of abnormally hyperphosphorylated tau protein, another trademark of this disease . Both patterns bring about neuronal degeneration, being associated with the progress of disease symptoms.…”

“…disease. [17][18][19][20] Both patterns bring about neuronal degeneration, being associated with the progress of disease symptoms.T he enzyme glycogen synthase kinase 3-beta (GSK-3b)h as emergeda sa ni mportant biological target for this hypothesis, as it is directly relatedt ot heset wo patterns. [11,21,22] Thus, selective GSK-3b inhibition, which prevents tau hyperphosphorylation and decreases Ab production,m ay be an effective therapeutic approach for the treatment of AD.…”