Acetylcholinesterase Receptor Research Articles

The Effects of Lamium garganicum L. Subsp. lasioclades (Stapf.) R. Mill Plant Against Fibroblast (U2OS Cell), Acetylcholinesterase, Glutathione S-Transferase: An In Vitro, In Silico Biological Activity Screening Study.

In this study, some biological activities of extracts of Lamium garganicum subsp. lasioclades (Lgl) have been evaluated as well as identified the phenolic composition. Concentration ranges of 31.25, 62.5, 125, 250, and 500µg/mL were applied to determine the extract's anticancer properties. Significant results were obtained against the osteosarcoma cell line (U2OS cell) compared to normal human umbilical vein endothelial cells (HUVEC). To determine the antioxidant activities, ABTS, DPPH, FRAP, and CUPRAC methods were studied in vitro. Enzyme inhibition effects of methanol extract against the glutathione S-transferase (GST) and acetylcholinesterase (AChE) enzymes were investigated. IC50 values were calculated as 12.96µL/mL for AChE and 13.02µg/mL for GST, respectively. The phenolic contents of the plant extract were analyzed by HPLC. The interaction mechanisms of protein-ligand complexes formed by AChE and GST receptors with gallic acid and rutin were investigated by molecular docking studies. The stability of the complexes formed between receptors and ligands was confirmed by root mean square deviation (RMSD), root mean square fluctuation (RMSF), number of average hydrogen bonding interactions (Hb), and radius of gyration (Rg) analyses obtained from 100ns molecular dynamics simulations.

In Silico Assessment of the Insecticidal and Herbicidal Potential of Silichristin Isolated from Silybum Marianum: Pharmacokinetic-Toxicity properties, Molecular Docking, and Molecular Dynamics

The present study aims to evaluate the pesticidal potential of a series of novel silichristin analogues isolated from silybum marianum using in silico approaches, focusing on their effects on the 4-hydroxyphenylpyruvate dioxygenase (HPPD) and acetylcholinesterase (AChE) receptors. A combinatorial library of 729 silichristin derivatives was constructed and virtual screening was performed to evaluate their pharmacokinetic and toxicity properties. Molecular docking analyses were performed to assess the binding affinity of the most potent candidates with target proteins. Our findings revealed that all selected compounds exhibited activity against both HPPD and AChE, with SIL3 and SIL7 demonstrating the lowest binding free energies (-8.4 and -7.9 kcal/mol, respectively). Further investigation via molecular dynamic simulation indicated that SIL3 and SIL7remained stable within the HPPD and AChE active sites, with RMSD values consistently below 2Å throughout the simulation. Overall, these results suggest that the newly identified silichristin derivatives hold promise as anti-pesticide agents.

Neuroprotection by 4R-cembranoid against Gulf War Illness-related Chemicals is mediated by ERK, PI3K, and CaMKII pathways

Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist).To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.

Benzyloxychalcone Hybrids as Prospective Acetylcholinesterase Inhibitors against Alzheimer's Disease: Rational Design, Synthesis, In Silico ADMET Prediction, QSAR, Molecular Docking, DFT, and Molecular Dynamic Simulation Studies.

Acetylcholinesterase inhibitors (AChEIs) are crucial therapeutic targets for both the early and severe stages of Alzheimer's disease (AD). Chalcones and their chromone-based derivatives are well-known building blocks with anti-Alzheimer properties. This study synthesized 4-benzyloxychalcone derivatives and characterized their structures using IR, 1H NMR, 13C NMR, and HRMS. Additionally, the synthesized 4-benzyloxychalcone derivatives were tested for anti-acetylcholinesterase (AChE) activity. The synthesized compounds outperformed galantamine, which is used as a positive control against acetylcholinesterase. Utilizing an acetylcholinesterase (AChE) receptor (PDB ID: 4EY7)-chalcone derivative (12a-c), a molecular docking investigation was performed on the synthesized compounds. The goal was to predict the binding sites and energies of the derivatives with respect to the receptor amino acids. The dynamic behavior of the ligand-receptor complex resulting from the interaction of the best docking compounds 12a and 12c with the acetylcholinesterase receptor was used to analyze the stability via MD simulation. MM/GBSA and MM/PBSA were used to calculate free binding energies using snapshots from system trajectories. Advanced computational approaches incorporating long-range corrections were utilized to calculate the molecular characteristics of chalcone derivatives 12a-c at the DFT/wB97XD/6-311++G(d,p) level. We used the molecular electrostatic surface potential (MESP) with high-quality data and visualization to find the most active site in these molecules. Reactivity descriptors, including the condensed Fukui function, chemical hardness (η), dual descriptors, chemical potential (μ), and electrophilicity (ω), were calculated for the chalcone derivatives.

Molecular docking and molecular dynamics simulation revealed potential compounds in Salvia miltiorrhiza for inhibiting enzymes and receptors in Alzheimer’s disease

Alzheimer’s disease is an age-related neurodegenerative disorder that leads to cognitive and functional decline. Potential target proteins for managing Alzheimer’s disease include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Beta-secretase cleavage enzyme (BACE1) and N-methyl-D-aspartate (NMDA) receptors. In this study, we conducted in silico evaluations of the inhibitory effects of Salvia miltiorrhiza’s compounds on AChE, BuChE, BACE1, and NMDA receptors. The Lipinski's rule of five was employed to compare phytochemicals with drug-like and non-drug-like properties. Based on previous publications, we compiled a list of 30 compounds from S.miltiorrhiza with potential for improving Alzheimer’s disease. Among these 30 compounds, six natural compounds exhibited potential inhibition of all four target proteins. Five of these six compounds, namely Tanshinone I, Tanshinone IIA, Isotanshinone I, Dihydroisotanshinone I, and Dihydroisotanshinone II, possessed drug-like properties, good absorption potential, and the ability to cross the blood-brain barrier. In conclusion, these five compounds show the highest potential as future drug candidates for the treatment of Alzheimer’s disease.

In silico analysis of the use of solanine derivatives as a treatment for Alzheimer's disease

Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences. It becomes more severe with age and is associated with cardiovascular disease, hypertension, and diabetes. Beta-amyloid plaques and hyper phosphorylated Tau protein buildup are common clinical findings. Misfiling of amyloid precursor protein (APP) and Amyloid beta peptide (Aβ) proteins contributes to Alzheimer's disease. Enzyme Acetylcholinesterase enzyme interacts with amyloid-beta, enhancing its accumulation in insoluble plaques, leading to successful treatment for Alzheimer's disease primarily based on lowering this enzyme. Treatments include using the Rivastigmine for mild, moderate, or severe Alzheimer's disease, which inhibits acetylcholinesterase, but may cause side effects; Solanine derivatives, nightshade toxin, it is cholinesterase inhibitory, may mitigate Alzheimer's illness is progressing. In this research utilized a molecular docking program, which is a computer's computational ability to determine the optimal position for a specific compound to bind to a protein or target, forming a target-ligand complex and displaying biological activity and aiding in the development of effective anti-AD treatments and understanding AD pathological mechanisms. The study examined complexes of 3LII (Acetylcholinesterase receptor) in the A and B chain with Solanine and Rivastigmine derivatives, using an in-silico approach. PyRx default sorter was used to improve docking accuracy. Four compounds were selected based on their higher binding affinities in chain A and B. The results showed that Solanine derivatives (alpha-Solanine, Beta1-Solanine and Beta2-Solanine) have higher binding strength (−9.0,-9.3 and −8.6) than Rivastigmine (−7.2) in chain A, and also the binding strength was high for the Solanine derivatives (alpha-Solanine, Beta1-Solanine, and Beta2-Solanine) (−9.0,-8.8 and −8.9) is higher than Rivastigmine (−6.0) in the chain B. Solanine derivatives showed higher binding strength with acetylcholinesterase, potentially for to reduce the progression of the disease.

Benincasa hispida Alleviates Stress and Anxiety in a Zebrafish (Danio rerio) Model.

The Ayurvedic medical system uses fruits of the Benincasa hispida plant to treat mental diseases, including schizophrenia. The goal of the current study was to assess the aqueous extract of B. hispida fruit's ability to relieve stress and anxiety induced in zebrafish models using neuropharmacological evaluation, which included determining behavioral parameters in tests such as the T-maze, open tank test (OTT), and light-dark preference test (LDPT). After measuring the zebrafish survival rate for 96 h, the LC50 was found to be 5 µg. AChE (acetylcholinesterase) inhibitory activity and the status of antioxidant enzymes (SOD, CAT, and LDH) were also used to evaluate the toxicity. Furthermore, the administration of the aqueous extract of B. hispida fruit increased the frequency of entry and duration of time spent in the bright section, suggesting a noteworthy reduction in levels of stress and anxiety. Additionally, the antistress and antianxiety activity was confirmed by the docking studies' mechanism of action, which involves the AChE receptor binding stability of the homogalactaconan molecule found in the aqueous extract of B. hispida fruit. Overall, the findings of this study demonstrated that the aqueous extract of B. hispida fruit is a viable therapeutic molecule for the creation of novel drugs and the treatment of stress since it has the therapeutic advantage of reversing the negative effects of stress and anxiety.

The looming threat of profenofos organophosphate and microbes in action for their sustainable degradation.

Organophosphates are the most extensively used class of pesticides to deal with increasing pest diversity and produce more on limited terrestrial areas to feed the ever-expanding global population. Profenofos, an organophosphate group of non-systematic insecticides and acaricides, is used to combat aphids, cotton bollworms, tobacco budworms, beet armyworms, spider mites, and lygus bugs. Profenofos was inducted into the system as a replacement for chlorpyrifos due to its lower toxicity and half-life. It has become a significant environmental concern due to its widespread presence. It accumulates in various environmental components, contaminating food, water, and air. As a neurotoxic poison, it inhibits acetylcholinesterase receptor activity, leading to dizziness, paralysis, and pest death. It also affects other eukaryotes, such as pollinators, birds, mammals, and invertebrates, affecting ecosystem functioning. Microbes directly expose themselves to profenofos and adapt to these toxic compounds over time. Microbes use these toxic compounds as carbon and energy sources and it is a sustainable and economical method to eliminate profenofos from the environment. This article explores the studies and developments in the bioremediation of profenofos, its impact on plants, pollinators, and humans, and the policies and laws related to pesticide regulation. The goal is to raise awareness about the global threat of profenofos and the role of policymakers in managing pesticide mismanagement.

Molecular Docking Study of Caffeic Acid as Acetylcholinesterase Inhibitor

Abstract: Acetylcholinesterase (AChE) receptor is a receptor that has been widely used as a potential drug target for Alzheimer's disease. Caffeic acid is a phenolic compound that had been experimentally proven to be an inhibitor of AChE. In this study, 100 molecular docking simulations were performed to study the interaction of caffeic acid in inhibiting AChE. The molecular docking simulations were performed using YASARA software with an in-house developed plug-in. Redocking results showed that there were 99 out of 100 docking poses had an RMSD value of ≤ 2.000 Å, which indicated that the molecular docking procedure could be used for further processes. The molecular docking of caffeic acid showed that all docking poses had an RMSD value of ≤ 2.000 Å relative to the best pose of the first simulation, revealing that there was only one dominant docking pose in the AChE active site. Caffeic acid interacted favorably in the AChE active site with binding energy of about -8.022 kcal/mol. Its interactions were stabilized by hydrophobic and pi-anion interactions, in which some of the interactions resemble the same interaction of the native ligand.
 Keywords: Acetylcholinesterase, Alzheimer's disease, caffeic acid, molecular docking

Assessment of the impacts of GABA and AChE targeting pesticides on freshwater invertebrate family richness in English Rivers

Globally, riverine system biodiversity is threatened by a range of stressors, spanning pollution, sedimentation, alterations to water flow, and climate change. Pesticides have been associated with population level impacts on freshwater invertebrates for acute high-level exposures, but far less is known about the chronic impact of episodic exposure to specific classes of pesticides or their mixtures. Here we employed the use of the UK Environment Agency's monitoring datasets over 40 years (covering years 1980 to 2019) to assess the impacts of AChE (acetylcholinesterase) and GABA (gamma-aminobutyric acid) receptor targeting pesticides on invertebrate family richness at English river sites. Concentrations of AChE and GABA pesticides toxic to freshwater invertebrates occurred (measured) across 18 of the 66 river sites assessed. For one of the three river sites (all found in the Midlands region of England) where data recorded over the past 40 years were sufficient for robust modelling studies, both AChE and GABA pesticides associated with invertebrate family richness. Here, where AChE total pesticide concentrations were classified as high, 46 of 64 invertebrate families were absent, and where GABA total pesticide concentration were classified as high, 16 of 64 invertebrate families were absent. Using a combination of field evidence and laboratory toxicity thresholds for population relevant endpoints we identify families of invertebrates most at risk in the selected English rivers to AChE and GABA pesticides. We, furthermore, provide strong evidence that the absence of the invertebrate family Polycentropodidae (caddisfly) from one field site is due to exposure effects to AChE pesticides.

In vitro and in silico cholinesterase inhibitory potential of metabolites from Laurencia snackeyi (Weber-van Bosse) M. Masuda.

Alzheimer's disease (AD) is a neurodegenerative disease that causes deterioration in intelligence and psychological activities. Yet, till today, no cure is available for AD. The marine environment is an important sink of bioactive compounds with neuroprotective potential with reduced adverse effects. Recently, we collected the red algae Laurencia snackeyi from Terumbu Island, Malaysia which is known to be rich in halogenated metabolites making it the most sought-after red algae for pharmaceutical studies. The red alga was identified based on basic morphological characteristics, microscopic observation and chemical data from literature. The purplish-brown algae was confirmed a new record. In Malaysia, this species is poorly documented in Peninsular Malaysia as compared to its eastern continent Borneo. Thus, this study intended to investigate the diversity of secondary metabolites present in the alga and its cholinesterase inhibiting potential for AD. The extract inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 14.45 ± 0.34 g mL-1 and 39.59 ± 0.24 g mL-1, respectively. Subsequently, we isolated the synderanes, palisadin A (1), aplysistatin (2) and 5-acetoxypalisadin B (3) that was not exhibit potential. Mass spectrometry analysis detected at total of 33 additional metabolites. The computational aided molecular docking using the AChE and BChE receptors on all metabolites shortlisted 5,8,11,14-eicosatetraynoic acid (31) and 15-hydroxy-1-[2-(hydroxymethyl)-1-piperidinyl]prost-13-ene-1,9-dione (42) with best inhibitory properties, respectively with the lowest optimal combination of S-score and RMSD values. This study shows the unexplored potential of marine natural resources, however, obtaining sufficient biomass for detailed investigation is an uphill task. Regardless, there is a lot of potential for future prospects with a wide range of marine natural resources to study and the incorporation of synthetic chemistry, in vivo studies in experimental design. The online version contains supplementary material available at 10.1007/s13205-023-03725-6.

In silico exploration of promising heterocyclic molecules against both acetylcholinesterase and butyrylcholinesterase enzymes

We aimed to further explore the relationship between heterocyclic molecules and their associated biological activities for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A dataset of 36 heterocycles was used to predict the activity of AChE and BChE inhibitors (the pIC50 values ranged from 7.84 to 12.49). A quantitative structure-activity relationship (QSAR) study was generated with the help of four different models (BMA, MNLR, MLR, and ANN). Four of the models were statistically acceptable based on both internal and external validation. The descriptors used in the models were similar to the X-ray structures of the target-ligand complexes, which made it possible to predict the pIC50 for AChE and BChE enzymes. Five selected molecules (compounds 6 (C21H21F3N4O), compound 7 (C22H23F3N4O), and compound 8 (C22H23F3N4O2) belong to the oxadiazole derivative group; compound 16 (C17H13ClN2O3) is classified into the chemical structures of different N, O, and S-based heterocycle groups; and compound 25 (C19H17NO2) pertains to the pyrimidine derivative group) possessed high pIC50 values for AChE and BChE enzymes (pIC50 values for AChE and BChE ranged from 9.01 to 10.32). The range of docking scores between the AChE and BChE receptors and their respective candidates was from −8.1 to −9.2 kcal/mol. The pharmacokinetics, biological activities, and physicochemical properties of five selected compounds supported their ability to protect against AD because they are not toxic, have a cholinergic effect, can cross the blood-brain barrier, and are well absorbed by the gastrointestinal tract. Communicated by Ramaswamy H. Sarma

Phytochemical composition, in vitro bioactivity evaluation and in silico molecular docking study of fruit essential oils of Zanthoxylum armatum DC collected from Himalayan region of Uttarakhand, India

The present research aimed to analyze the nematicidal and insecticidal activity of the essential oil obtained from the fruits of Zanthoxylum armatum collected from Gumma village of Dharchula and Chandak village of Pithoragarh. After extraction via hydro distillation, the essential oils were subjected to GC–MS for their compositional analysis. A total of 10 and 13 components were identified for the Dharchula and Pithoragarh collection respectively. Linalool (32.86 %) was the major component in collection from Dharchula whereas it was totally absent in that of collection from Pithoragarh which has trans-sabinene hydrate (11.7 %) as its major component. Essential oils were tested against Meloidogyne incognita for their nematicidal activity and inhibition of egg hatching in laboratory conditions. It was found that the activity of Z. armatum from Dharchula shows high mortality of Meloidogyne incognita and more inhibition to the egg hatching. When tested for insecticidal activity against Lipaphis erysimi, collection from Dharchula presented stronger activity compared to Pithoragarh collection as shown by their LC50 values 0.006 and 0.165 µL/mL respectively after 36 hrs. The in silico PASS study and molecular docking study was conducted to screen the nematicidal and insecticidal potential of the major components on acetylcholinesterase receptors. Results showed good binding affinities and attributed the strongest inhibitory effect to verbenone for the target protein.

Identification of promising inhibitory heterocyclic compounds against acetylcholinesterase using QSAR, ADMET, biological activity, and molecular docking

Heterocyclic compounds exert diverse functions, especially acetylcholinesterase (AChE) inhibition. Thus, identifying the association between their detailed structures and biological activities is important to the development of novel medications for Alzheimer’s disease (AD) treatment. In this study, diverse sets of 120 potent and selective heterocyclic compounds (-log[the half‑maximal inhibitory concentration] (pIC50) values ranged from 8.01 to 12.50) were used to develop quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR), multiple nonlinear regression (MNLR), Bayesian model average (BMA), and artificial neural network (ANN) models. The models' robustness and stability have been assessed using both internal and external methodology. ANN outperforms MLR, MNLR, and BMA according to external validation. The molecular descriptors incorporated into the model were in satisfactory correlation with the AChE receptor-ligand complex X-ray structures, making the model interpretable and predictive. Three selected compounds exert drug-like characteristics (pIC50 values ranged from 11.01 to 11.17). The binding affinity between the optimal compounds and the AChE receptor (RCSB ID 3LII) ranged from − 7.4 to − 8.8 kcal/mol. Remarkably, the pharmacokinetics, physicochemical properties, and biological activities of compound 25 (C23H32N2O2, PubChem CID 118727071, pIC50 value = 11.17) were found to be consistent with its therapeutic effects in AD due to its cholinergic and non-toxic nature, non-P-glycoprotein, high gastrointestinal absorption, and capability to penetrate the blood-brain barrier.

In-silico docking and molecular dynamic introspective study of multiple targets of AChE with Rivastigmine and NMDA receptors with Riluzole for Alzheimer’s disease

The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of −8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of −9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer’s disease. Communicated by Ramaswamy H. Sarma

AChE as a spark in the Alzheimer's blaze - Antagonizing effect of a cyclized variant.

The amyloid precursor protein (APP), presenilin 1 (PS1), amyloid beta (Aβ), and GSK3 are the effectors, which are significantly associated with progression of Alzheimer's Disease (AD) and its symptoms. A significant protein, acetylcholinesterase (AChE) becomes dysfunctional as a result of cholinergic neuronal loss in AD pathology. However, certain associated peptides potentiate the release of primary neuropathological hallmarks, i.e., senile plaque and neurofibrillary tangles (NFTs), by modulating the alpha 7 acetylcholinesterase receptor (α7nAChR). The AChE variants, T30 and T14 have also been found to be elevated in AD patients and mimic the toxic actions of pathological events in patients. The manuscript discusses the significance of AChE inhibitors in AD therapeutics, by indicating the disastrous role of molecular alterations and elevation of AChE, accompanied with the downstream effects instigated by the peptide, supported by clinical evidence and investigations. The cyclized variant of AChE peptide, NBP14 has been identified as a novel candidate that reverses the harmful effects of T30, T14 and Aβ, mainly calcium influx, cell viability and AChE release. The review aims to grab the attention of neuro-researchers towards the significance of triggering effectors in propagating AD and role of AChE in regulating them, which can potentially ace the development of reliable therapeutic candidates, similar to NBP14, to mitigate neurodegeneration.

Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.

Toxicological and molecular adverse effect of Illicium verum fruit constituents toward Bradysia procera.

Bradysia procera, a ginseng stem fungus gnat, is one of the most serious insect pests of Korean ginseng (Panax ginseng), causing significant damage to plant growth. The goal of this study was to determine the toxicity and mechanism of action of phenylpropanoids (trans-anethole and estragole) isolated from the methanol extract and hydrodistillate of Illicium verum fruit against third-instar larvae and eggs of Bradysia procera. The filter-paper mortality bioassay revealed that estragole [median lethal concentration (LC50 ) = 4.68 g/cm2 ] has a significant fumigant effect, followed by trans-anethole (LC50 = 43.92 g/cm2 ). However, estragole had the lowest toxic effect when compared to commercially available insecticides. After 7 days, estragole and trans-anethole at 75 g/cm2 inhibited egg hatchability up to 97% and 93%, respectively. At 0.09 g/cm2 , insecticides had an inhibitory effect on egg-hatching ability ranging from 88% to 94%. Furthermore, in both closed and open containers, these active constituents were able to consistently induce vapor-phased toxicity. Both estragole and trans-anethole have the ability to inhibit acetylcholinesterase (AChE), which is involved in neurotransmitter function. However, the active constituent estragole from I. verum fruit acted as a potent AChE inhibitor and had a slightly lower effect on cyclic adenosine monophosphate (AMP) than octopamine alone. This finding suggests that estragole may influence Bradysia procera neurotransmitter function via both the AChE and octopaminergic receptors. More research is needed to demonstrate the potential applications of I. verum fruit-derived products as potential larvicides and ovicides for Bradysia procera population control. © 2022 Society of Chemical Industry.

Abstract A079: The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses

Abstract The human genome contains multiple sites of quadruplex (G4) arrangements, with over-representation in promoter regions of many oncogenes. Small molecule G4 stabilization down-regulates the transcription of these genes, leading to selective inhibition of cancer cell growth and anti-tumor activity. We have developed a number of novel G4-binding small molecules. QN-302, the most potent, has significant in vivo activity in animal models for pancreatic cancer and is currently in pre-clinical development with Qualigen Therapeutics. The effects of QN-302 have been examined on (1) a panel of cardiac function receptors, (2) heart rate in vivo, and (3) on the histopathology of organs from treated animals. QN-302 was initially screened in a series of in vitro industry-standard CEREP receptor binding assays. The few apparent indications of significant receptor binding were examined in vivo by means of ELISA assays. Cardiac function was examined using a cardiac heart-beat monitor attached to animals treated with QN-302 and compared to animals dosed with a vehicle control. QN-302 gave negative results in CEREP assays, apart from micromolar inhibition of acetylcholinesterase (ACE) and muscarinic (MUSC) receptors. There was no significant hERG receptor inhibition. There was no significant inhibition of ACE and MUSC receptors in vivo. Heart rate experiments, run at both the proposed therapeutic dose of 1mg/kg and at elevated levels, did not show significant deviations from values for the vehicle control arm. Histopathology of heart, liver and brain tissues from QN-302 treated animals, did not show any deleterious effects from the drug. The lack of effects on ACE and MUSC receptors in vivo, together with the absence of effects on heart, liver and brain tissue from treated animals and the normality of heart rate during treatment, demonstrate that treatment of MIA-Paca2 tumor-bearing mice with QN-302 does not have a cardio-, nephro- or neurotoxic burden at therapeutic doses. QN-302 is bio-available at therapeutic doses and is currently in pre-clinical development with Qualigen Therapeutics Inc Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A079.

Nontoxic and Naturally Occurring Active Compounds as Potential Inhibitors of Biological Targets in Liriomyza trifolii

In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to investigate insect gut proteases and the interactions of PIs for the development of resistance against insects. We, herein, report an in silico study of (disodium 5'-inosinate and petunidin 3-glucoside), (calcium 5'-guanylate and chlorogenic acid), chlorogenic acid alone, (kaempferol-3,7-di-O-glucoside with hyperoside and delphinidin 3-glucoside), and (myricetin 3'-glucoside and hyperoside) as potential inhibitors of acetylcholinesterase receptors, actin, α-tubulin, arginine kinase, and histone receptor III subtypes, respectively. The study demonstrated that the inhibitors are capable of forming stable complexes with the corresponding proteins while also showing great potential for inhibitory activity in the proposed protein-inhibitor combinations.