BACE1 Research Articles

In Silico and In Vitro Evaluation of Quinoline Derivatives as Potential Inhibitors of AChE, BACE1, and GSK3β for Neurodegenerative Diseases Treatment.

Neurodegenerative diseases are characterized by the structural and functional loss of neurons, affecting populations worldwide. Enzymes like acetylcholinesterase (AChE), beta-site APP cleaving enzyme-1 (BACE1), and glycogen synthase kinase 3-beta (GSK3β), contribute to their development. This study explores in silico and in vitro assays of quinoline analogues as potential inhibitors of these enzymes. In silico analyses highlighted derivative SQ6 as the most potent inhibitor for all proteins. In vitro assays confirmed that the quinoline derivatives had a modulating action on the three targets. SQ6 showed a significant AChE inhibition of 94.6%. Regarding the inhibition of GSK3β and BACE1, derivatives SQ6-SQ9, with the quinoline linked to the sulfonamide nitrogen, showed inhibition values above 40%. SQ7 and SQ9 were not considered cytotoxic for cell proliferation in human glioblastoma, and SQ6 did not show cytotoxicity at 7.8 and 3.9 µg mL-1. In murine fibroblasts, SQ6 presented a result similar to that observed for cell proliferation in human glioblastoma, while SQ7 and SQ9 were non-cytotoxic below 62.5 µg mL-1. These findings underscore compound SQ6 as the first potential multitarget enzyme inhibitor for treating neurodegenerative diseases.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, InVitro, and InVivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.

Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM to 800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

Acorus tatarinowii alleviates D-galactose-induced Alzheimer’s-like disease cognitive impairment and Aβ-induced pericytes dysfunction in mice

Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer’s disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD

Ambroxol Improves Amyloidogenic, NF‐κB, and Nrf2 Pathways in a Scopolamine‐Induced Cognitive Impairment Rat Model of Alzheimer's Disease

ABSTRACTAmbroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and nuclear factor erythroid 2‐related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y‐Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1‐40, Amyloid beta peptide 1‐42, acetylcholinesterase, beta‐secretase 1 (BACE1), total tau, and p‐tau], inflammatory markers [NF‐κB, tumor necrosis factor alpha (TNF‐α), interleukin 6 (IL‐6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO‐1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1‐40, amyloid beta 1‐42, total tau, p‐tau, NF‐κB, IFN‐γ, IL‐6, and TNF‐α decreased significantly. There was a significant increase in the levels of HO‐1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF‐κB and senescence‐associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF‐κB signaling pathways in AD.

Gamma Wave Stimulation Affects BACE1 Levels and Promotes the Transition of Microglia from M1 State to M2 State

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and it presents with the hallmark neuropathological features of amyloid-beta (Aβ) plaques, tau tangles and active neuroinflammation. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key mediator of increased Aβ, has been identified as the primary enzymatic source for production of this pathologic peptide while reactive microglial cells contribute to ongoing neurodegeneration perhaps through activation into their aggressive M1 state. The present study endeavors for the first time to address how gamma wave stimulation modulates BACE1 and microglial polarization (from M1 to beneficial M2) in different AD models. We hypothesize that gamma wave stimulation will reduce BACE1, decrease Aβ plaque burden and shift microglials towards M2 phenotype leading to reduced neuroinflammation and maintain cognitive function. This study will target mouse models of AD which have undergone gamma wave stimulation and its effects on BACE1 expression, microglial polarisation markers, Aβ plaque load and cognitive performance. Hypotheses the treatment will reduce BACE1 activity, decrease M1/M2 microglial ratio, improve cognitive performance and delay Aβ plaque accumulation These data suggest promising therapeutic strategies for neuroinflammation and amyloidogenesis in AD.

Evaluation of Selected Plant Phenolics via Beta-Secretase-1 Inhibition, Molecular Docking, and Gene Expression Related to Alzheimer’s Disease

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.

BACE Inhibitor Clinical Trials for Alzheimer's Disease.

The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer's disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer's disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.

BACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives.

Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.

Implantable Intraocular Fluorescence Sensor for Visualized Monitoring of Alzheimer's Disease

AbstractWith an increase in the older individuals, the global incidence of Alzheimer's disease (AD) is increasing. Early diagnosis of AD necessitates long‐term monitoring; however, conventional diagnostic methods such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are unsuitable for frequent use because of infrastructure limitations. The eye, connected to the brain via the optic nerve, offers a potential window for monitoring neurodegenerative diseases. This study presents a novel system for continuous intraocular monitoring using a fluorescent aptamer‐conjugated intraocular lens (FAIOL). FAIOL emits fluorescent signals in the presence of beta‐secretase‐1 (BACE1), an enzyme associated with amyloid beta 1–42 production. These signals can be analyzed using mobile phone applications. In vitro, experiments demonstrates that FAIOL responded to BACE1 by detecting low concentrations of the target molecule over extended periods. Ex vivo tests using porcine eyeballs shows an increase in the fluorescence signal intensity by more than 8% within 5 h in the presence of BACE1. The integrated image analysis program reduces sensor noise and provides numerical signal values, facilitating a straightforward interpretation. FAIOL holds significant potential as an innovative platform for the early diagnosis and long‐term monitoring of AD and promises improved patient outcomes through timely intervention and ongoing surveillance.

An Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.

Bioactive compounds and in vitro biological properties of Arthrospira platensis and Athrospira maxima: a comparative study

Cyanobacteria, especially Arthrospira, are valuable resources of nutrients and natural pigments with many beneficial health-related properties. This study optimized the extraction conditions of Arthrospira to achieve high phenolic contents and antioxidant activities. Under optimized extraction conditions, the bioactive compounds (phenolics and pigment components), antioxidant activities, and inhibitions of the key enzymes relevant to some non-communicable diseases were compared between Arthrospira platensis and Arthrospira maxima. Optimized extraction conditions were determined as 2 h shaking time, 50 °C extraction temperature, and 1% (w/v) solid-to-liquid ratio, giving effective phenolic and phycocyanin contents using aqueous extraction, while 80% (v/v) aqueous ethanolic extraction provided high total chlorophyll content. Most antioxidant activities were higher using 80% (v/v) aqueous ethanolic extracts. Both Arthrospira species inhibited the key enzymes involved in controlling non-communicable diseases including hyperlipidemia (lipase), diabetes (α-amylase, α-glucosidase, and dipeptidyl peptidase-IV), Alzheimer’s disease (acetylcholinesterase, butyrylcholinesterase and β-secretase), and hypertension (angiotensin-converting enzyme). High inhibitory activities were detected against β-secretase (BACE-1), the enzyme responsible for β-amyloid plaque formation in the brain that acts as a significant hallmark of Alzheimer’s disease. Arthrospira extract and donepezil (Alzheimer’s disease drug) synergistically inhibited BACE-1, suggesting the potential of Arthrospira extracts as effective BACE-1 inhibitors. Interestingly, A. maxima exhibited higher bioactive compound contents, antioxidant activities, and key enzyme inhibitions than A. platensis, indicating high potential for future food and medicinal applications.

Exploring the Benzazoles Derivatives as Pharmacophores for AChE, BACE1, and as Anti-Aβ Aggregation to Find Multitarget Compounds against Alzheimer’s Disease

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles’ activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.

Cheminformatics-driven prediction of BACE-1 inhibitors: Affinity and molecular mechanism exploration

The β-secretase, sometimes referred to as BACE1 or Asp2, is the enzyme responsible for initiating the production of Aβ by breaking down the amyloid precursor protein. Hence, BACE is a pivotal target for pharmacological intervention aimed at diminishing the production of Aβ in Alzheimer's disease (AD). We did a quantitative structure-activity relationship (QSAR) study on 1235 compounds that had been experimentally reported as BACE-1 inhibitors (Ki) to find the target molecule and structural patterns linked to blocking the BACE-1 receptor. The OECD-recommended genetic algorithm-multiple linear regression (GA-MLR) QSAR model strikes a good balance between being able to make accurate predictions and understanding how things work. It achieves high values for many evaluation metrics, including R2tr = 0.8047, Q2LMO = 0.802, R2ex = 0.805, CCCex = 0.891, Q2-F1=0.801, Q2-F2=0.799, and Q2-F3=0.815. The mechanistic interpretation of QSAR has identified some nitrogen atoms that are required to block beta-secretase and make it less effective at doing its job. A positively charged aromatic carbon atom has a more significant impact on beta-secretase-1 inhibition. The docking study showed that the catalytic dye residues Asp32 and Asp228 become protonated when compound 27 is present, but they stay unprotonated when compound 27 is not present. These rings of pyrazine and pyridine interact hydrophobically with Tyr71 and Ile118 residues, confirming the pharmacophoric features seen in the QSAR data. We examined the stability of both the protein-ligand complex and the apo-protein. The apoprotein had an average gyration radius of 22.13, whereas the protein-ligand complex had an average gyration radius of 22.91. No changes were made to the results from the molecular docking, molecular dynamics (MD) simulation, MMGBSA (Molecular Mechanics Generalized Born Surface Area), or DFT analyses. Therefore, the current work could effectively contribute to the future development of BACE inhibitors in medication design.

QSAR Modeling for Predicting Beta-Secretase 1 Inhibitory Activity in Alzheimer's Disease with Support Vector Regression

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, with the accumulation of β-amyloid (Aβ) plaques playing a key role in its progression. Beta-Secretase 1 (BACE1) is a crucial enzyme in Aβ production, making it a prime therapeutic target for AD treatment. However, designing effective BACE1 inhibitors has been challenging due to poor selectivity and limited blood-brain barrier permeability. To address these challenges, we employed a machine learning approach using Support Vector Regression (SVR) in a Quantitative Structure-Activity Relationship (QSAR) model to predict the inhibitory activity of potential BACE1 inhibitors. Our model, trained on a dataset of 7,298 compounds from the ChEMBL database, accurately predicted pIC50 values using molecular descriptors, achieving an R² of 0.690 on the testing set. The model's performance demonstrates its utility in prioritizing drug candidates, potentially accelerating drug discovery. This study highlights the effectiveness of computational approaches in optimizing drug discovery and suggests that further refinement could enhance the model’s predictive power for AD therapeutics.

Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation

Amyloid β protein (Aβ) deposition has been implicated as the molecular driver of Alzheimer’s disease (AD) progression. The modulation of the formation of abnormal aggregates and their post-translational modification is strongly suggested as the most effective approach to anti-AD. Beta-site APP-cleaving enzyme 1 (BACE1) acts upstream in amyloidogenic processing to generate Aβ, which rapidly aggregates alone or in combination with acetylcholinesterase (AChE) to form fibrils. Accumulated Aβ promotes BACE1 activation via glycogen synthase kinase-3β (GSK-3β) and is post-translationally modified by glutaminyl cyclase (QC), resulting in increased neurotoxicity. A novel multi-target inhibitor as a potential AD agent was identified using an in silico approach and experimental validation. Magnolia officinalis, which showed the best anti-AD activity in our preliminary study, was subjected to analysis, and 82 compounds were studied. Among 23 compounds with drug-likeness, blood–brain barrier penetration, and safety, honokiol emerged as a lead structure for the inhibition of BACE1, AChE, QC, and GSK-3β in docking and molecular dynamics (MD) simulations. Furthermore, honokiol was found to be an excellent multi-target inhibitor of these enzymes with an IC50 of 6–90 μM, even when compared to other natural single-target inhibitors. Taken together, the present study is the first to demonstrate that honokiol acts as a multiple enzyme inhibitor with an excellent pharmacokinetic and safety profile which may provide inhibitory effects in broad-range areas including the overproduction, aggregation, and post-translational modification of Aβ. It also provides insight into novel structural features for the design and discovery of multi-target inhibitors for anti-AD.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aβ) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE)ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n=1556) received umibecestat (50 or 15mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Computational identification of promising therapeutics via BACE1 Targeting: Implications for Alzheimer's disease.

Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aβ. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1.