Potent Acetylcholinesterase Inhibitors Research Articles

New 3-amino-2-thioxothiazolidin-4-one-based inhibitors of acetyl- and butyryl-cholinesterase: synthesis and activity.

Aim: 2-Thioxothiazolidin-4-one represents a versatile scaffold in drug development. The authors used it to preparenew potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors that can be utilized, e.g., to treat Alzheimer's disease. Materials & methods: 3-Amino-2-thioxothiazolidin-4-one was modified at the amino group or active methylene, using substituted benzaldehydes. The derivatives were evaluated for inhibition of AChE and BChE (Ellman's method). Results & conclusion: The derivatives were obtained with yields of 52-94%. They showed dual inhibition with IC50 values from 13.15μM; many compounds were superior to rivastigmine. The structure-activity relationship favors nitrobenzylidene and 3,5-dihalogenosalicylidene scaffolds. AChE was inhibited noncompetitively, whereas BChE was inhibited with a mixed type of inhibition. Molecular docking provided insights into molecular interactions. Each enzyme is inhibited by a different binding mode.

Glycosyl Thiourea: Synthesis, Cyclization, Reaction, Molecular Docking, and Evaluation as Potential Acetylcholinesterase Inhibitors

Glycosyl Thiourea: Synthesis, Cyclization, Reaction, Molecular Docking, and Evaluation as Potential Acetylcholinesterase Inhibitors

Neuropathological Mechanisms of Alzheimer's Disease: Complications and Potential Treatments

Alzheimer’s Disease (AD) is a neurodegenerative disorder that targets the brain and disrupts vital processes of neural networks causing the decline of cognitive function. The main pathological mechanisms responsible for the development of Alzheimer’s are the tau and amyloid-beta proteins. These proteins are detrimental because they form plaque and neurofibrillary tangles that aggregate within the brain. Biomarkers and diagnostic tools are utilized to detect Alzheimer’s within a patient. These devices can potentially detect the onset of Alzheimer’s early, reducing the severity of symptoms. Throughout studies of various research articles, certain potential AD treatments were analyzed to determine their efficacy. Galantamine was found to be a potent inhibitor of acetylcholinesterase and more effective than rivastigmine and donepezil. A controversial herbal supplement, Ginkgo Biloba, was examined to determine its relevance in reducing the severity of Alzheimer’s. Research findings support that the supplement's efficacy is inconclusive as trials have not been able to provide significant evidence as to whether or not Ginkgo Biloba is effective in the case of Alzheimer’s. By investigating the impact of prospective treatments on the mechanisms of Alzheimer’s, this extensive research aims to provide evidence to handle the effects of the disease and determine significant treatments to ensure the quality of healthcare for all patients distressed by Alzheimer’s Disease.

Phenolics from Nigella sativa L. straw: Characterization and insecticidal activity against Agrotis ipsilon (Hüfnagel)

The excessive production of food and agro-waste has become a significant problem for society, the economy, and the environment. To meet the growing demand for food free from harmful synthetic insecticides, a recent study has investigated the potential use of an ethanolic extract obtained from the straw of Nigella sativa L., a byproduct of seed collection, as a bioinsecticide. The study also evaluated its in-vitro and in-silico acetylcholinesterase (AChE) inhibitory potential against the Agrotis ipsilon (Hufnagel) moth species, which is known to cause damage to various crops and ornamental plants. The high-performance liquid chromatography examination revealed that the ethanolic N. sativa straw extract contained 18 phenolics, including 3 simple phenols, 8 phenolic acids, and 7 flavonoids. Catechol (330.14 μg/ml), chlorogenic (169.23 μg/ml), and gallic (110.93 μg/ml) acids were the predominant phenolics. On the other hand, catechin (94.07 μg/ml), naringenin (91.99 μg/ml), and rutin (78.16 μg/ml) were the major flavonoids identified in the extract. The insecticidal activity of the extract against the 4th larval instar of A. ipsilon was evaluated using four concentrations (1.25–10 %). The study found that higher extract concentrations led to increased mortality in the larvae. Specifically, the concentration of 10 % resulted in the highest mortality rate of 96.67 %. Lower concentrations of 5 %, 2.5 %, and 1.25 % resulted in mortality rates of 51.11 %, 18.89 %, and 9.17 %, respectively. The extract also showed higher activity against AChE in larval tissue, with an inhibition percentage of 65.2 % after 24 h of treatment. Docking experiments confirmed that ellagic acid and apigenin had higher binding affinity than the control (lanate). These results demonstrate the potential of utilizing agricultural waste like N. sativa straw to create innovative and sustainable bioinsecticides.

Inhibition of Acetylcholinesterase with Novel 1, 3, 4, Oxadiazole Derivatives: A Kinetic, In Silico, and In Vitro Approach.

Alzheimer's disease (AD) is a neurological disease that disturbs the memory, thinking skills, and behavior of the affected person. AD is a complex disease caused by the breakdown of acetylcholine via acetylcholinesterase (AChE). The present study aimed to assess the synthetic inhibitors of AChE that could be used to treat AD. For this purpose, synthetic compounds of oxadiazole derivatives (15-35) were evaluated and identified as promising inhibitors of AChE, exhibiting IC50 varying between 41.87 ± 0.67 and 1580.25 ± 0.7 μM. The kinetic parameters indicated that all the studied compounds bind to the allosteric site and decrease the efficiency of the AChE enzyme. In silico docking analysis showed that the majority of the compounds interact with the anionic subsite and Per-Arnt-Sim domain of AChE and are stabilized by various bonds including π-π and hydrogen bonding. The stability of the most potent compounds 16 and 17 with AChE interaction was confirmed by molecular dynamics simulations. Moreover, all compounds exhibited concentration-dependent calcium (Ca2+) antagonistic and spasmolytic activities. Among the whole series of oxadiazole derivatives, compounds 16 and 17 displayed the highest activities on spontaneous and potassium (K+)-induced contraction. Therefore, the AChE inhibitory potential, cytotoxicity safe profile, and Ca2+ antagonistic ability of these compounds make them potential therapeutic agents against AD and its associated problems in the future.

Hydrazone-sulfonate hybrids as potential cholinesterase inhibitors: design, synthesis and molecular modeling simulation.

Aim: Design and synthesis of a series of hydrazone-sulfonate hybrids, 5a-r. Methodology: The inhibitory properties of the synthesized compounds against acetylcholinesterase and butyrylcholinesterase were evaluated using donepezil as the reference standard. Results & conclusion: Compound 5e was identified as the most potent inhibitor of acetylcholinesterase (IC50=9.30μM), and compound 5i was the most potent inhibitor of butyrylcholinesterase (IC50=11.82μM). To confirm the safety of the most potent hits at the used doses, toxicological bioassays were conducted. Molecular docking was performed and the tested derivatives were found to fit well in the active sites of both enzymes. This study provides valuable insights into the potential of hydrazone-sulfonate hybrids as drug candidates.

Novel harmine derivatives as potent acetylcholinesterase and amyloid beta aggregation dual inhibitors for management of Alzheimer’s disease

In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Aβ 1 − 42 aggregation. Notably, compounds 13 and 17d displayed potent drug − likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC50 = 58.76 nM and 89.38 nM, respectively) as well as Aβ aggregation (IC50 = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ 1 − 42−induced SH − SY5Y damage, while maintaining low toxicity in SH − SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual − targeted candidates for treating AD.

Antioxidant, α-amylase and acetylcholinesterase inhibitory potential of Mazus pumilus (Japanese Mazus) extract: An in-vitro and in-silico study

Plant-derived secondary metabolites possess diverse biological activities that are beneficial to humans. Modern medications used for diabetes and Alzheimer’s often cause side effects, prompting reliance on traditional alternatives. Therefore, we aimed to uncover the potential of Mazus pumilus in countering diabetes and Alzheimer’s by in-vitro inhibition of α-amylase and AChE. Additionally, antioxidant activity and phytochemical analyses were performed. Mazus pumilusThe plant was extracted sequentially using n-hexane, ethyl acetate, dichloromethane, methanol, and water. The methanolic fraction, notably, manifested marked antioxidant efficacy against DPPH and ABTS radicals. Subsequently, this extract evinces noteworthy inhibitory attributes against α-amylase and AChE, respectively, in a competitive manner. Moreover, the bioactive phytoconstituents present in the methanolicextracts were determined through GC–MS analysis, and subsequent computational molecular docking studies revealed that these compounds strongly bound to the active site of both α-amylase and AChE. The calculated least binding energies, for α-amylase and AChE, underscore the viability of the molecular interactions. In conclusion, the antioxidant, antidiabetic, and anti-Alzheimer attributes of Mazus pumilus extract likely emanate from the synergistic interplay of its bioactive phytoconstituents. A comprehensive in-vitro and in-vivo study is essential to fully explore the anti-diabetic and anti-Alzheimer potential of secondary metabolites of Mazus pumilus.

2a-Alkylnorlitebamines and (7a,8)-didehydroisohomoaporphines: Synthesis and antiacetylcholinesterase activity verified via in silico molecular docking

As N-alkyl-norlitebamines have been demonstrated to possess antiacetylcholinesterase activity, this study aimed to prepare related analogs to verify their structure–activity relationship. The compounds with the chemical skeletons of 2a-alkylnorlitebamines (6b–6e) and (7a,8)-didehydroisohomoaporphines (8b–8e, 9a, and 10b–10e) were designed and synthesized. In silico molecular docking of the 13 compounds on the acetylcholinesterase template indicated that 8a and 10b showed the highest docking scores (ΔG) (−20.56 Kcal/mol and −19.76 Kcal/mol, respectively). The reaction of peracylsecolaurolitsines under the modified Bischler–Napieralski procedure and subsequent NaBH4 reduction yielded 7a-alkyl- B homoaurolitsines 8a−8e, possessing a new skeleton, besides the expected 2a-alkyl-norlitebamines 10b−10e. Among these compounds, the two with the highest docking scores [Δ7a (8)- B homoaurolitsine (8a) and 2a-methyl-norlitebamine (10b)] showed better inhibitory activities against acetylcholinesterase (eel) with IC50 value of 24.71 μM and 26.13 μM, respectively. Therefore, compounds 8a and 10b could serve as leads for exploring potential acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease.

Liquid-phase surface enhanced Raman spectroscopic detection of nerve agent motifs using gold nanostars

Organophosphates and their derivatives are deadly compounds owing to their ability to disrupt key regulators of biological activity and neuronal transmission. As such, typical uses for synthetic and natural organophosphates include nerve agents and toxic pesticides. Organophosphate pesticides alone are estimated to make up around 3–10 % of the international pesticide poisoning deaths, or approximately 5–15,000 deaths annually. Mechanistically, they irreversibly bind to acetylcholinesterase, a crucial enzyme dealing with motor control that has minimal structural differences across all walks of life explaining the universal toxicity of organophosphates. In this study, we present the fabrication of a nanoparticle-based detection method to detect two commonly used organophosphates: dimethyl methylphosphonate (DMMP) which is used as the starting material for many chemical warfare agent syntheses, and dimethyl chlorophosphate (DMCP) which is a potent acetylcholinesterase inhibitor and readily harmful to the body through dermal absorption or ingestion. We further demonstrate accurate and precise micromolar detection of these organophosphates with a simple portable Raman spectrometer, and additionally demonstrate the ability to easily detect and distinguish between both analytes in a heterogenous solution using this methodology. The nanoparticle-based detection relies on a method of Surface-enhanced Raman spectroscopy (SERS) in liquid phase. Throughout the duration of the experiment, liquid solutions and a portable Raman spectrometer were utilized to demonstrate efficacy of the detection method even with instruments and conditions that would be typically seen in the environment of organophosphate use, such as in a less technology developed warfare or rural setting. Through this detection method, we found a reliable fingerprint peak for DMMP (710.63 cm−1) with a limit of detection (LOD) of 9.11 mM and a limit of quantitation (LOQ) of 27.6 mM, with 1.5 ± 0.11 SERS. Similarly, for DMCP (755.97 cm−1), a LOD of 17.79 mM, a LOQ of 53.90 mM, and 1.3 ± 0.01 SERS enhancement were observed. Our theoretical studies predict possible SERS enhancement of >104, with significantly stronger signal compared with spherical nanoparticles. Time and pH studies show that our detection method is both fast and facile, without any required field modifications for baseline detection.

Acetylcholinesterase inhibition studies of alkaloid components from Crinum asiaticum var. sinicum: in vitro assessments by molecular docking and molecular dynamics simulations

Alkaloids are among the most important and best-known secondary metabolites as sources of new drugs from medicinal plants and marine organisms. A phytochemical investigation of the whole plant of Crinum asiaticum var. sinicum resulted in the isolation of seven alkaloids (1–7), including one new dimeric compound, bis-(-)-8-demethylmaritidine (1). Their structures were elucidated using NMR and HR-ESI-MS. The absolute configuration of new compound 1 was established by circular dichroism spectroscopy. All isolated compounds were evaluated for their inhibitory effects on acetylcholinesterase (AChE) activity in vitro. Among them, compound 1 exhibited the most potent AChE inhibition. Moreover, molecular docking and molecular dynamics simulations were carried out for the most active compound to investigate their binding interactions and dynamics behavior of the AChE protein-ligand complex. Therefore, compound 1 may be a potential candidate for effectively treating Alzheimer’s disease.

Structurally diverse brefeldin A derivatives as potent and selective acetylcholinesterase inhibitors from an endophytic fungus Penicillium brefeldianum F4a

Nine previously undescribed brefeldin A (BFA) derivatives (1–9), together with one known compound 4-epi-brefeldin A (10), were isolated from an endophytic fungus Penicillium brefeldianum F4a. The chemical structures were elucidated using NMR and HRESIMS. ECD analysis and Mosher's method were used to confirm the absolute configurations of 1–9. The inhibitory activity of all isolated BFA derivatives (1–10) on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was evaluated in vitro. The bioassay results suggested that neobrefeldin (1) and brefeldin H (2) exhibited higher potent and selective AChE inhibitory activity (IC50 = 0.12 and 0.28 μM) than the therapeutic drug galantamine for Alzheimer's disease (AD) (IC50 = 0.66 µM), whereas only neobrefeldin (1) displayed weak inhibitory activity against BuChE (IC50 = 175.04 µM). Moreover, a molecular docking analyses was performed and showed compounds 1 and 2 were dual binding site AChE inhibitors. It is worth noting that neobrefeldin (1) showed a better binding affinity with the peripheral anionic site through the hydrogen bonding interaction with Tyr124 than brefeldin H (2), resulting in better AChE inhibitory activity. These findings not only provide a promising AChE inhibitor neobrefeldin (1) for developing agents against early AD, but also provide a valuable perspective for better understanding its AChE inhibition activity.

A Comparative Analysis of Radical Scavenging, Antifungal and Enzyme Inhibition Activity of 3'-8″-Biflavones and Their Monomeric Subunits.

Biflavonoids are dimeric forms of flavonoids that have recently gained importance as an effective new scaffold for drug discovery. In particular, 3'-8″-biflavones exhibit antiviral and antimicrobial activity and are promising molecules for the treatment of neurodegenerative and metabolic diseases as well as cancer therapies. In the present study, we directly compared 3'-8″-biflavones (amentoflavone, bilobetin, ginkgetin, isoginkgetin, and sciadopitysin) and their monomeric subunits (apigenin, genkwanin, and acacetin) and evaluated their radical scavenging activity (with DPPH), antifungal activity against mycotoxigenic fungi (Alternaria alternata, Aspergillus flavus, Aspergillus ochraceus, Fusarium graminearum, and Fusarium verticillioides), and inhibitory activity on enzymes (acetylcholinesterase, tyrosinase, α-amylase, and α-glucosidase). All the tested compounds showed weak radical scavenging activity, while antifungal activity strongly depended on the tested concentration and fungal species. Biflavonoids, especially ginkgetin and isoginkgetin, proved to be potent acetylcholinesterase inhibitors, whereas monomeric flavonoids showed higher tyrosinase inhibitory activity than the tested 3'-8″-biflavones. Amentoflavone proved to be a potent α-amylase and α-glucosidase inhibitor, and in general, 3'-8″-biflavones showed a stronger inhibitory potential on these enzymes than their monomeric subunits. Thus, we can conclude that 3'-8″-dimerization enhanced acetylcholinesterase, α-amylase, and α-glucosidase activities, but the activity also depends on the number of hydroxyl and methoxy groups in the structure of the compound.

Exploring Medicinal Herbs' Therapeutic Potential and Molecular Docking Analysis for Compounds as Potential Inhibitors of Human Acetylcholinesterase in Alzheimer's Disease Treatment.

Background and Objectives: Alzheimer's disease (AD) stands as a pervasive neurodegenerative ailment of global concern, necessitating a relentless pursuit of remedies. This study aims to furnish a comprehensive exposition, delving into the intricate mechanistic actions of medicinal herbs and phytochemicals. Furthermore, we assess the potential of these compounds in inhibiting human acetylcholinesterase through molecular docking, presenting encouraging avenues for AD therapeutics. Materials and Methods: Our approach entailed a systematic exploration of phytochemicals like curcumin, gedunin, quercetin, resveratrol, nobiletin, fisetin, and berberine, targeting their capability as human acetylcholinesterase (AChE) inhibitors, leveraging the PubChem database. Diverse bioinformatics techniques were harnessed to scrutinize molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and adherence to Lipinski's rule of five. Results: Results notably underscored the substantial binding affinities of all ligands with specific amino acid residues within AChE. Remarkably, gedunin exhibited a superior binding affinity (-8.7 kcal/mol) compared to the reference standard. Conclusions: These outcomes accentuate the potential of these seven compounds as viable candidates for oral medication in AD treatment. Notably, both resveratrol and berberine demonstrated the capacity to traverse the blood-brain barrier (BBB), signaling their aptitude for central nervous system targeting. Consequently, these seven molecules are considered orally druggable, potentially surpassing the efficacy of the conventional drug, donepezil, in managing neurodegenerative disorders.

Novel chalcone derivatives of ursolic acid as acetylcholinesterase inhibitors: Synthesis, characterization, biological activity, ADME prediction, molecular docking and molecular dynamics studies

Acetylcholinesterase (AChE) is a critical target in the prevention of Alzheimer's Disease (AD) progression. With the goal of developing potential acetylcholinesterase inhibitors, a new series chalcone derivatives of ursolic acid (4–11) were synthesized and characterized by means of their NMR, FTIR and HRMS spectral data. hAChE inhibition abilities of all compounds were tested in vitro. Compounds 10, 8 and 7 showed high hAChE inhibitory potential with the IC50 values of 1.82, 4.65 and 5.36 µM respectively. When compared to the standard inhibitor (Galantamine, IC50= 1.96 µM), compound 10 was the most potent derivative. After performing kinetic studies, KM constant and Vmax value of hAChE were determined as 0.059 mM and 0.052 EU/ml respectively. Inhibition type of compound 10 was found as competitive and Ki constant was calculated as 1.31 ± 0.18 µM. The inhibition mechanism of compounds was predicted by molecular docking, MM/GBSA analysis, molecular dynamics simulation and ADME studies. Molecular docking studies showed that compounds 10, 8, and 7 have highest binding scores (-9.235, -8.827, -8.645 kcal/mol, respectively), while the standard inhibitor galantamine exhibited binding score of -5.106 kcal/mol. According to the MM/GBSA analysis, compounds 10 and 7 displayed binding free energies of -46.19 and -49.19 kcal/mol, respectively, which were higher than the standard's binding free energy of -41.82 kcal/mol. Molecular dynamic simulations were confirmed successful placement of the compounds 10, 8 and 7 in the active site of AChE. The in silico ADME predictions indicated that compound 10 has acceptable potency as a drug in treatment of AD.

Structure-based design of new N-benzyl-piperidine derivatives as multitarget-directed AChE/BuChE inhibitors for Alzheimer's disease.

The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energyestimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.

Mechanistic insights and therapeutic implications of novel pyrazoline derivatives on antioxidant and enzymatic inhibitory activities

One of the major features of medicinal chemistry, is the synthesis of novel compounds, and the assessment of their biological activities for potential therapeutic applications. As a contribution to this filed of interest, the present work examines the effects of newly synthesized pyrazoline derivatives. To this end, four pyrazoline derivatives were synthesized and evaluated for their antioxidant activities and enzymatic inhibitory in vitro against acetylcholinesterase (AChE) and tyrosinase. All the synthetized compounds 2a–2d all displayed a moderate to potent antioxidant activity. For the enzymatic inhibitory activity, compound 2a exerted the most potent acetylcholinesterase inhibition with an IC50 value of (IC50 = 3.93 ± 0.52 µM) which is twice greater than the standard drug, Galantamine (IC50 = 6.27 ± 1.15 µM), whereas, compound 2a was determined as the best inhibitor among the synthesized compounds for the tyrosinase enzyme with an IC50 value of (32.65 ± 2.30 μM). Density Functional Theory (DFT) calculations were performed to determine the compound's properties, and molecular docking studies were conducted to discuss potential interactions between the most active compound (2a) and active sites of proteins AChE (PDB: 1ACL) and tyrosinase (PDB: 2Y9X). Based on in silico predictions of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and pharmacokinetic parameters, it is suggested that these compounds could potentially exhibit favorable oral bioavailability. The paper offers promising insights into the therapeutic potential of these pyrazoline derivatives, particularly compound 2a. It encourages further investigation into the practical application of these findings, possibly leading to new therapeutic avenues in the treatment of diseases associated with acetylcholinesterase and tyrosinase.

New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking.

The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N'-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC50 value was 9.01 µM compared to that for quercetin, with IC50 = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme.

Empirical and molecular docking-based screening of heterocyclic compounds to identify potential acetylcholinesterase inhibitors to treat Alzheimer’s disease and its histology

Empirical and molecular docking-based screening of heterocyclic compounds to identify potential acetylcholinesterase inhibitors to treat Alzheimer’s disease and its histology

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