Correction to Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer’s Disease
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PROVIDER: S-EPMC9835155 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Project description:The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3β inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3β inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 μM), BACE1 (48.3% at 20 μM), and GSK3β (40.3% at 10 μM). Furthermore, 1c showed good blood-brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aβ-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3β lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.
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Project description:Alzheimer's disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer's disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets. These candidates were discovered by using state-of-the-art methods as molecular calculations (molecular docking and molecular dynamics), artificial neural networks and multilinear regression models. These methods were used for virtual screening of the publicly available library containing more than twenty thousand compounds. The experimental testing enabled us to confirm a multitarget drug candidate active at low micromolar concentrations against two targets, e.g., AChE and BACE1.
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Project description: Not available
| S-EPMC7418795 | biostudies-literature
Project description:Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.
| S-EPMC10142303 | biostudies-literature
Project description:A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 μM for eeAChE; IC50 = 0.16 μM for hAChE), and it was also the best inhibitor to AChE-induced Aβ aggregation (29.02% at 100 μM) and an efficient inhibitor to self-induced Aβ aggregation (30.67% at 25 μM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).
| S-EPMC6844382 | biostudies-literature
Project description:Alzheimer׳s disease (AD) is one of the most common dementias showing slow progressive cognitive decline. Progression of intracerebral accumulation of beta amyloid (Aβ) peptides by the action of amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the degradation of Acetylcholinesterase (AChE) the main pathological characteristics of AD. Therefore, it is of interest to evaluate the importance of fisetin (a flavonol that belongs to the flavonoid group of polyphenols) binding with AChE, ABAD and BACE1 proteins. Docking experiment of fisetin with these proteins using two different tools namely iGEMDOCK and FlexX show significant binding with acceptable binding values. Thus, the potential inhibitory role of fisetin with AD associated proteins is documented.
| S-EPMC4209364 | biostudies-literature
Project description:Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ₁₋₄₂ induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ₁₋₄₂ neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
| S-EPMC3618987 | biostudies-literature
Project description:Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.
| S-EPMC3533290 | biostudies-literature
Project description:The β-site APP cleaving enzyme 1 (BACE1) is an important target for causing Alzheimer's disease (AD), due to the brain deposition peptide amyloid beta (Aβ) require cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, but treatments of AD still have side effect in recent therapy. This study utilizes the world largest traditional Chinese medicine (TCM) database and database screening to provide potential BACE1 inhibited compound. Molecular dynamics (MD) simulation was carried out to observe the dynamics structure after ligand binding. We found that Triptofordin B1 has less toxicity than pyrimidine analogue, which has more potent binding affinity with BACE1. For trajectory analysis, all conformations are tending to be stable during 5000 ps simulation time. In dynamic protein validation, the residues of binding region are still stable after MD simulation. For snapshot comparison, we found that Triptofordin B1 could reduce the binding cavity; the results reveal that Triptofordin B1 could bind to BACE1 and better than control, which could be used as potential lead drug to design novel BACE1 inhibitor for AD therapy.
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Project description:In continuation of our program aimed at the discovery and development of natural product-based insecticidal agents, a series of novel nereistoxin derivatives containing phosphonate were synthesized and characterized by 31P, 1H, 13C NMR and HRMS. The bioactivities of the derivatives were evaluated for the acetylcholinesterase (AChE) inhibition potency and insecticidal activity. The AChE inhibitory effects of the derivatives were investigated using the in vitro Ellman method. Half of the compounds exhibited excellent inhibition of AChE. All the compounds were assessed for insecticidal activities against Mythimna separate (Walker) and Rhopalosiphum padi in vivo. Some derivatives displayed promising insecticidal activity against Rhopalosiphum padi. Compounds 5b and 6a displayed the highest activity against R. padi, showing LC50 values of 17.14 and 18.28 μg mL-1, respectively, close to that of commercial insecticide flunicotamid (LC50 = 17.13 μg mL-1). Compound 9g also showed notable insecticidal activity, with an LC50 value of 23.98 μg mL-1. Additionally, the binding modes of the active compounds 5b, 6a and 9g with AChE were analyzed in-depth though molecular docking and the intrinsic reasons for the differences in the strength of the compound's activities were elucidated. In summary, our findings demonstrate the potential of these nereistoxin derivatives as promising candidates for the development of novel pesticides.
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