Acetylcholinesterase Protein Research Articles

Coumarin modified Silatrane: A potent probe for Hg(II) ion Detection, biological evaluation and Acetylcholinesterase inhibition

Mercury contamination poses significant threats to human health, aquatic ecosystems and various living organisms. Effective detection methods are essential for monitoring such contamination. In this investigation, coumarin-derivatized silatrane (CS) was synthesized and meticulously characterized using 1H NMR, 13C NMR and mass spectrometry. The CS compound exhibited outstanding performance in detecting Hg(II), showing excellent selectivity and sensitivity even in the presence of other metal ions with very low limit of detection value (LOD). Furthermore, the CS system exhibited promising performance in analyzing real water samples, yielding a recovery rate exceeding 95 %. Beyond its detection prowess, CS displayed notable biological properties, including significant radical scavenging activity. Molecular docking studies revealed its potential as an inhibitor of acetylcholinesterase (AChE) protein, suggesting a prospective role in combating Alzheimer disease’s disease.

Effects of Ficus exasperata on neurotransmission and expression of BDNF, tau, ACHE and BACE in diabetic rats

Diabetes mellitus, a chronic metabolic disorder, has significant global health implications, particularly due to its neurological complications, such as diabetic neuropathy. This condition increases the risk of neurodegenerative diseases by affecting peripheral nerves and cognition. Ficus exasperata, known for its neuroprotective properties, shows promise as a therapeutic option for addressing these complications. This study evaluates the effects of methanol extract of Ficus exasperata (MEFE) on neurotransmission and the expression of Tau, brain-derived neurotrophic factor (BDNF), acetylcholinesterase (ACHE), and Beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) in alloxan-induced diabetic Wistar rats. The controlled experimental design involved 20 Wistar rats divided into four groups (n = 5): control, diabetic untreated, diabetes + MEFE (200 mg/kg), and diabetes + insulin (0.3 IU). The methanol extract was prepared using cold maceration, and an aliquot was subjected to gas chromatography-mass spectrometry. Constituents of MEFE were docked with neurologic receptors. Blood glucose levels were measured using the glucose oxidase method, and neurotransmitter levels, antioxidants, oxidative stress markers, and the expression of Tau, BDNF, ACHE, and BACE were assessed using standard procedures and qRT-PCR. Data were analyzed using one-way ANOVA at P < 0.05. Results indicated that MEFE significantly reduced fasting blood glucose levels compared to untreated diabetic rats. In silico docking identified kaur-16-ene, a constituent of MEFE, as having the highest binding affinity for NMDA, TrkB, mAchR and nAchR receptors, indicating its neuroprotective potential. MEFE also enhanced antioxidant enzyme levels (SOD, GPx, catalase) while reducing oxidative stress markers (MDA, 8-OHdG). Gene expression analysis revealed that MEFE modulates the expression of Tau, BDNF, ACHE, and BACE, suggesting its potential to influence neurodegenerative pathways associated with diabetic neuropathy. Ficus exasperata demonstrates significant therapeutic potential in managing diabetic neuropathy and related cognitive impairments by modulating neurotransmission, protein expression, and antioxidant defenses.

Role of bone marrow mesenchymal stem cell-derived exosomes in reducing neurotoxicity and depression-like behaviors induced by doxorubicin in rats.

Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited nowadays due to its neurobiological side effects associated with depression. Bone marrow mesenchymal stem cells (BM-MSCs) derived exosomes are a promising regenerative therapy. In this study, we investigated the therapeutic potentiality of BM-MSCs derived exosomes against the neurotoxicity induced by DOX. Twenty-four male albino rats were divided equally in to three groups as follow: group 1 (control), group 2 (rats injected intraperitoneally (i.p|) with DOX at a dose 2.5mg/Kg), and group 3 (rats injected with DOX and BM-MSCs derived exosomes i.p at a dose 1.5ml/Kg). During the experiment the behavior tests were noted, after three weeks rats were sacrificed, serum and brain samples were collected for biochemical, molecular and histopathological examinations. The results revealed that DOX causing impairment of the locomotor and increasing the anxiety like behavior of rats, marked neuropathological changes, significant elevation of MDA content and TNF-α concentration, reduction of phospholipase (PLD) and acetylcholinesterase (AChE) protein concentration in addition, there were up regulation of JNK, NF-κB and p38 genes and down regulation of Erk1. Exosomal therapy improved the substantial neurotoxicity of DOX through modulating the markers involved in the neurotoxic signalling pathway of DOX that resulting in improving the pathological lesions and the animal behaviours.

Transcriptome analysis reveals mechanisms of metabolic detoxification and immune responses following farnesyl acetate treatment in Metisa plana

Metisa plana is a widespread insect pest infesting oil palm plantations in Malaysia. Farnesyl acetate (FA), a juvenile hormone analogue, has been reported to exert in vitro and in vivo insecticidal activity against other insect pests. However, the insecticidal mechanism of FA on M. plana remains unclear. Therefore, this study aims to elucidate responsive genes in M. plana in response to FA treatment. The RNA-sequencing reads of FA-treated M. plana were de novo-assembled with existing raw reads from non-treated third instar larvae, and 55,807 transcripts were functionally annotated to multiple protein databases. Several insecticide detoxification-related genes were differentially regulated among the 321 differentially expressed transcripts. Cytochrome P450 monooxygenase, carboxylesterase, and ATP-binding cassette protein were upregulated, while peptidoglycan recognition protein was downregulated. Innate immune response genes, such as glutathione S-transferases, acetylcholinesterase, and heat shock protein, were also identified in the transcriptome. The findings signify that changes occurred in the insect’s receptor and signaling, metabolic detoxification of insecticides, and immune responses upon FA treatment on M. plana. This valuable information on FA toxicity may be used to formulate more effective biorational insecticides for better M. plana pest management strategies in oil palm plantations.

Exploring the Therapeutic Potential of Alkaloids in Alzheimer's Disease Management.

Alkaloids are important phytoconstituents obtained from various plant sources. The study's primary goal is to assess the anti-Alzheimer potential of alkaloids using a molecular docking study. Alzheimer's disease (AD) is considered a gradual decline in memory, reasoning, decision-making, orientation to one's physical surroundings, and language. The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. The structures of various alkaloids were drawn using Chem Draw Software, PDB was retrieved from the RCSB PDB database, and molecular docking study was performed on Molergo Virtual Docker. The potential alkaloids were identified with anti-Alzheimer potency. Reserpine, vinblastine, ergotamine, and tubocurarine were found to exhibit potential anti-Alzheimer potency.

Neuroprotective effect of long-term resistance physical exercise against memory damage elicited by a lipopolysaccharide-induced neuroinflammation model in malerats.

Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.

Secondary Bioactive Metabolites from Foods of Plant Origin as Theravention Agents against Neurodegenerative Disorders.

Neurodegenerative disorders (NDDs) such as Alzheimer's (AD) and Parkinson's (PD) are on the rise, robbing people of their memories and independence. While risk factors such as age and genetics play an important role, exciting studies suggest that a diet rich in foods from plant origin may offer a line of defense. These kinds of foods, namely fruits and vegetables, are packed with a plethora of powerful bioactive secondary metabolites (SBMs), including terpenoids, polyphenols, glucosinolates, phytosterols and capsaicinoids, which exhibit a wide range of biological activities including antioxidant, antidiabetic, antihypertensive, anti-Alzheimer's, antiproliferative, and antimicrobial properties, associated with preventive effects in the development of chronic diseases mediated by oxidative stress such as type 2 diabetes mellitus, respiratory diseases, cancer, cardiovascular diseases, and NDDs. This review explores the potential of SBMs as theravention agents (metabolites with therapeutic and preventive action) against NDDs. By understanding the science behind plant-based prevention, we may be able to develop new strategies to promote brain health and prevent the rise in NDDs. The proposed review stands out by emphasizing the integration of multiple SBMs in plant-based foods and their potential in preventing NDDs. Previous research has often focused on individual compounds or specific foods, but this review aims to present a comprehensive fingerprint of how a diet rich in various SBMs can synergistically contribute to brain health. The risk factors related to NDD development and the diagnostic process, in addition to some examples of food-related products and medicinal plants that significantly reduce the inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), are highlighted.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.

Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.

Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.

Effect of Dietary Tigernut on Acetylcholinesterase, Specific Acetylcholinester, and Total Protein Levels in Rabbit Brains of Different Genotupes

Effect of Dietary Tigernut on Acetylcholinesterase, Specific Acetylcholinester, and Total Protein Levels in Rabbit Brains of Different Genotupes

Sphingosine-1-Phosphate Receptor Modulator – Siponimod: An Evaluation to Ameliorate Aluminium Chloride Induced Behavioural Change and Biochemical effects

Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterised by the gradual loss of hippocampal and cortical neurons, resulting in diminished memory and cognitive function. Siponimod (SPM) a selective modulator of sphingosine 1-phosphate receptor subtype 1 and 5(S1P1,S1P5 receptors), was found to have neuroprotective effect in neurological disorders. The present study was conducted to evaluate its beneficial effects in AD. Materials and Methods: In-silico molecular docking and molecular dynamic simulation studies were carried to know its potential interactions with selected target proteins. In-vivo study was conducted inthirty rats divided randomly into five groups with six rats per group: Control group received Carboxy methyl cellulose; disease group were administered aluminium chloride (AlCl3);standard group received rivastigmine (RVST) with AlCl3; and the test groups received SPM (0.05mg/kg and 0.2mg/kg) with AlCl3. Morris water maze test and elevated plus maze was used to evaluate learning and memory. Behavioural changes and biochemical parameters estimation were performed at the end of experiment. Results: The molecular docking study using selected protein and ligands showed higher docking score and stable interactions at acetylcholinesterase (AChE) protein with SPM.Behavioural studies showed: decrease in transfer latency time in elevated plus maze; decrease in time to reach target platform and increase in time spent in target quadrant in Morris water maze test in SPM treated rats. Biochemical evaluation showed marked decrease in malondialdehyde (MDA), nitrite, myeloperoxidase (MPO)levels and increased antioxidant levels in SPM treated groups. SPM exhibited significant inhibitory activity onAChE. Conclusion: SPM was found to be effective in ameliorating AlCl3 induced AD. The observed benefits in restoring learning and memory were attributed to its inhibitory activity on AChE and its ability to suppress free radical mediated oxidative damage.

Identification of coumarin derivatives targeting acetylcholinesterase for Alzheimer's disease by field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, MM/GBSA, ADME and MD Simulation study

Alzheimer's disease (AD) leads to gradual memory loss including other compromised cognitive abilities. Acetylcholinesterase (AChE), an important biochemical enzyme from the cholinesterase (ChE) family, is recognized as primary pharmacological target for treating AD. Currently marketed drugs for AD treatment are primarily AChE inhibitors and coumarin derivatives comprising a wide variety of pharmacological activities have proved their efficacy towards AChE inhibition. Ensaculin (KA-672 HCl), a compound that belong to the coumarin family, is a clinical trial candidate for AD treatment. Therefore, a ligand library was prepared with 60 reported coumarin derivatives for field-based 3D-QSAR and pharmacophore modelling. The field-based 3D-QSAR model obtained at partial least square (PLS) factor 7, was the best validated model that predicted activity closer to original activity for each ligand introduced. The contour maps demonstrated spatial distribution of favourable and unfavorable steric, hydrophobic, electrostatic and H-bond donor and acceptor contours around coumarin nucleus. The best pharmacophore model, ADHRR_1 exhibited five essential pharmacophoric features of four different traits for optimum AChE inhibition. Virtual screening through ADHRR_1 accompanied with molecular docking and MM/GBSA identified 10 HITs from a 4,00,000 coumarin derivatives from PubChem database. HITs comprised docking scores ranging from −12.096 kcal/mol to −8.271 kcal/mol and compared with the reference drug Donepezil (-8.271 kcal/mol). ADME properties analysis led into detecting two leads (HIT 1 and HIT 2) among these 10 HITs. Molecular Dynamics Simulation indicated thermodynamic stability of the complex of lead compounds with AChE protein. Finally, thorough survey of the experimental results from 3D-QSAR modelling, pharmacophore modelling and molecular docking interactions led us to develop the lead formula I for future advancements in treating AD through AChE inhibitors.

Carthamus tinctorius seeds-Taraxacum coreanum combination attenuates scopolamine-induced memory deficit through regulation of inflammatory response and cholinergic function.

There is growing interest in herbal medicines for managing age-related diseases, such as Alzheimer's and Parkinson's. Safflower seeds (Carthamus tinctorius L. seeds, CTS) and dandelions (Taraxacum coreanum, TC) are widely used to treat bone- or inflammation-related diseases in Oriental countries. This study investigated the protective effect of the CTS-TC combination on scopolamine (Sco)-induced memory deficits through inflammatory response and cholinergic function. Moreover, marker components such as serotonin, N-(p-coumaroyl) serotonin, N-feruloylserotonin, chlorogenic acid, and chicoric acid in the CTS-TC combination were analyzed for their potential benefits on memory function. Water extracts of CTS, TC, and the CTS-TC combination at various ratios (4:1, 1:1, and 1:4) (100 mg/kg) were orally administered to mice for 14 days. Sco (1 mg/kg) was intraperitoneally injected into the mice before each behavioral test. T-maze and novel object recognition tests were conducted to monitor behavioral changes after the treatment. Western blotting was performed to detect protein expression. In addition, the presence of 5 biomarkers, serotonin, N-(p-coumaroyl) serotonin, N-feruloylserotonin, chlorogenic acid, and chicoric acid, was analyzed using high-performance liquid chromatography (HPLC). Behavioral tests showed that the CTS-TC combination enhanced memory function in Sco-injected mice. Inflammation-related proteins (inducible nitric oxide synthase, cyclooxygenase-2, and glial fibrillary acidic protein) were downregulated after treatment with the CTS-TC combination. The acetylcholinesterase protein expression was also downregulated. HPLC analysis revealed that N-feruloylserotonin and chicoric acid were the predominant components, followed by N-(p-coumaroyl) serotonin, chlorogenic acid, and serotonin. These findings suggest that the CTS-TC combination protects against Sco-induced memory deficits by inhibiting inflammatory responses and cholinergic dysfunction. N-feruloylserotonin and chicoric acid, along with N-(p-coumaroyl) serotonin, chlorogenic acid, and serotonin, might be biomarkers for the CTS-TC combination, and their effects on memory protection warrant further study.

Larvicidal Activity of Ethanol Extract of Cinnamomum sintoc Blume Bark against Aedes aegypti: Role of the Extract as an Acetylcholinesterase Enzyme Inhibitor

The display ponders evaluated the larvicidal exercises of ethanol bark extricates of Cinnamomum sintoc BI against the third instar hatchlings of Aedes aegypti. For superior understanding, this show ponders moreover examined the instrument of plant extricates against the hatchlings through in silico examination. Larvicidal exercises of plant extricate were considered within the extent of 0.01 to 0.1% and two control bunch with aquades and temephos within the research facility bioassays against early third instar hatchlings of A. aegypti. The mortality was checked and subjected to probit investigation to decide the deadly concentrations (LC50 and LC90) to murder 50 and 90% of the treated hatchlings of the particular species. Also, to examine the instrument, four dynamic compounds within the plant extricate with the most noteworthy substance analyzed in silico with the acetylcholinesterase protein in A. aegypti. The appears about appear expanding the concentration will increment the passing of the hatchlings and the viability of the extricate is found to be superior to temephos. The comes about of in silico investigation appeared that the two dynamic compounds in plant extricates, specifically α-copaene and γ-muurolene have a component of activity comparable to temephos. Both of these compounds work as inhibitors of acetylcholinesterase chemicals. Our information recommends that the bark ethanol extricate of C. sintoc BI have the potential to be utilized as a larvicidal operator for the control of the A. aegypti.

Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.

Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.

Design of a new potent Alzheimer's disease inhibitor based on QSAR, molecular docking and molecular dynamics investigations

A series of 32 molecules derived from 7-prenyloxy-2,3-dihydroflavanone and 5‑hydroxy-7-prenyloxy-2,3-dihydro-flavanone possessing an inhibitory activity against the Acetylcholinesterase (AChE) enzyme were studied using the structure-activity (QSAR) investigations. Electronic descriptors of studied molecules were calculated using Gaussian software using DFT method at the B3YP/6–31G(d, p) level. In addition, constitutional, physicochemical, and topological descriptors were calculated using Chem3D software.The best model obtained by the multiple linear regression (MLR) method was subjected to external and internal statistical validations. What is more, the applicability domain (ad) has been defined for the built model using Williams plot. We have designed new molecular structures similar to the basis of giving of the studied dataset and their activity is predicted by the built model. Then, the molecular docking was used to predict the affinity between the newly inhibitors candidates and the AChE protein. This study was completed by the molecular dynamic simulation (MDs) to predict the stability of the formed complexes, the RMSD and RMSF plots of studied complexes were analyzed.

In silico analyses of bioactive compounds extracted from ziziphus jujuba using supercritical CO2 extraction: Potential anti-anxiety and anti-Alzheimer’s disease

Background: Jujube (Chinese date) is a fruit with a pleasant, sweet taste, traditionally used as sedative to treat insomnia and anxiety. Objective: The study aims to explore the potential of these bioactive compounds in exerting anti-anxiety and anti-Alzheimer's disease effects. Methods: Molecular docking, ADME, and molecular dynamics studies were carried out for the green-extracted phytochemicals against acetylcholinesterase and Beta-amyloid proteins for Anti-Alzheimer’s disease effect and serotonin receptor for anti-anxiety activity. Our results suggest that compound (2,3,6,7-tetramethyl-10-(4-methylphenylsulfonyloxy)-1,4,4.alpha.,5,8,8a.beta.,9.b) showed good binding affinity of -10.3 with acetylcholinesterase (4EY7) as anti-Alzheimer’s disease and the compound andrographolide with serotonin transporter (6VRH) showed binding affinity of -9.7 for anxiety. Compounds with the best docking scores were subjected to molecular dynamic simulations.Results: These compounds revealed the best stability. Conclusion: These findings are promising for manufacturing new functional foods, nutraceuticals, food supplements, and/or pharmaceuticals which may play a good and safe role in treating Alzheimer disease and anxiety. While further biological studies must be carried out, our computational studies suggest that these compounds have potent activity.Keywords: Ziziphus jujuba; Bioactive compounds; Neurological disorders disease; Molecular docking, ADME and Molecular dynamics.

An exploration of binding of Hesperidin, Rutin, and Thymoquinone to acetylcholinesterase enzyme using multi-level computational approaches

Alzheimer’s disease, an intricate neurological disorder, is impacting an ever-increasing number of individuals globally, particularly among the aging population. For several decades phytochemicals were used as Ayurveda to treat both communicable and non-communicable diseases. Acetylcholinesterase (AChE) is a widely chosen therapeutic target for the development of early prevention and effective management of neurodegenerative diseases. The primary objective of the present study was to investigate the binding potential between Rutin Thymoquinone, Hesperidin and the FDA-approved drug Donepezil with AChE. Additionally, a comparative analysis was conducted. These phytochemicals were docked with the binding site of the AChE experimental complex. The molecular dockings demonstrated that the Hesperidinh showed a better binding affinity of −22.0631 kcal/mol. The ADME/T investigations revealed that the selected phytochemicals are non-toxic and drug-like candidates. Molecular dynamics simulations were implemented to determine the conformational changes of Rutin, hesperidin, Thymoquinone, and Donepezil complexed with AChE. Hesperidin and Donepezil were more stable than Rutin, Thymoquinone complexed with AChE. Next, essential dynamics and defining the secondary structure of protein were to determine the conformational changes in AChE complexed with selected phytochemicals during simulations. Overall, the MD Simulations demonstrated that all complexes in this study achieved stability until 100 ns of the simulation period was performed thrice. The structural analysis of AChE was done using multiple search engines to explore the molecular functions, biological processes, and pathways in which AChE proteins are involved and to identify potential drug targets for various diseases. This present study concludes that Hesperidin was found to be a more potent AChE inhibitors than Rutin, and further experiments are required to determine the effectivity of Hesperidin against neurodegenerative diseases. Communicated by Ramaswamy H. Sarma

Design of Acetylcholinesterase Inhibitors as Promising Anti‐Alzheimer's Agents Based on QSAR, Molecular Docking, and Molecular Dynamics Studies of Liquiritigenin Derivatives

AbstractCholinesterase inhibitors are promising drugs for the symptomatic treatment of Alzheimer's disease. In the current study, we explored the quantitative structure activity relationship (QSAR) of a series of Liquiritigenin derivatives recently assessed for their anti‐acetylcholinesterase activity. The multiple linear regression was applied to establish a QSAR model relating the biological activities of the studied compounds to their molecular descriptors. The QSAR model quality was evaluated by adopting Golbraikh and Tropsha's criteria. The obtained results highlight the fact that the developed model is perfectly valid (MSE=0.038; R2=0.789; R2adj=0.747; Q2CV=0.670; F=18.751) and exhibit high predictive power (R2test=0.760). Besides, Balaban Index (J), total energy (ET), dipole moment (μ) and electrophilicity index (ω) were identified to be the most relevant descriptors governing the anti‐acetylcholinesterase activity. By analyzing these molecular features, new Liquiritigenin derivatives with enhanced anti‐acetylcholinesterase activity were designed. Moreover, both molecular docking and molecular dynamics were performed to support the obtained results. In addition, the pharmacokinetics properties corresponding to the designed molecules were estimated. As a result, the compounds D10 and D13 were found to possess good pharmacokinetics properties and predicted to form stable complexes with the acetylcholinesterase protein, supporting their use as anti‐Alzheimer drug candidates.

Identification of potential inhibitors against Alzheimer-related proteins in Cordyceps militaris ethanol extract: experimental evidence and computational analyses.

Laboratory experiments were carried out to identify the chemical composition of Cordyceps militaris and reveal the first evidence of their Alzheimer-related potential. Liquid chromatography-mass spectrometry analysis identified 21 bioactive compounds in the ethanol extract (1-21). High-performance liquid chromatography quantified the content of cordycepin (0.32%). Bioassays revealed the overall anti-Alzheimer potential of the extract against acetylcholinesterase (IC50 = 115.9 ± 11.16µgmL-1). Multi-platform computations were utilized to predict the biological inhibitory effects of its phytochemical components against Alzheimer-related protein structures: acetylcholinesterase (PDB-4EY7) and β-amyloid protein (PDB-2LMN). In particular, 7 is considered as a most effective inhibitor predicted by its chemical stability in dipole-based environments (ground state - 467.26302 a.u.; dipole moment 11.598 Debye), inhibitory effectiveness ( - 13.6kcalmol-1), polarized compatibility (polarizability 25.8 Å3; logP - 1.01), and brain penetrability (logBB - 0.244; logPS - 3.047). Besides, 3 is promising as a brain-penetrating agent (logBB - 0.257; logPS - 2.400). The results preliminarily suggest further experimental attempts to verify the pro-cognitive effects of l(-)-carnitine (7). The online version contains supplementary material available at 10.1007/s13205-023-03714-9.