The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening

Ilg, Thomas; Cramer, Jörg; Lutz, Jürgen; Noack, Sandra; Schmitt, Harald; Williams, Heike; Newton, Trevor

doi:10.1016/j.ibmb.2011.04.003

Cited by 11 publications

(5 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural differences between Lucilia cuprina and human AChE have also led to the identification of 19 previously unknown non-carbamate, non-organophosphate inhibitors, which are up to 335-fold more potent against the L . cuprina enzyme than against human AChE ( Ilg et al 2011 ). Aryl methylcarbamates bearing a β-branched 2-alkoxy or 2-thioalkyl group were found to possess good selectivity for inhibition of A. gambiae AChE over human AChE ( Hartsel et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…AChE activity was determined by a modified Ellman’s method ( Anazawa et al 2003 , Ilg et al 2011 , Bu et al 2015b ). Preincubated with different compounds for 20 min at 4 °C and 10 min at room temperature, the purified AChE proteins or mite extracts were thoroughly centrifuged to remove the precipitate, followed by the transfer of each aliquot to the reaction wells.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae)

Wang

Cao

Lai

et al. 2023

Journal of Insect Science

View full text Add to dashboard Cite

The two-spotted spider mite, Tetranychus urticae Koch, has a broad host plant range and presents an extreme capacity for developing pesticide resistance, becoming a major economic pest in agriculture. Anticholinesterase insecticides still account for a big part of global insecticide sales. However, there is a growing concern about the serious resistance problems of anticholinesterase insecticides and their nontarget toxicity. In this study, structure-based virtual screening was performed to discover selective AChE inhibitors from the ChemBridge database, and 39 potential species-specific AChE inhibitor were obtained targeting T. urticae AChE, but not human AChE. Among them, compound No. 8 inhibited AChE from T. urticae, but not from human, and had an inhibitory activity comparable to that of eserine. Compound No. 8 had dose-dependent toxicity to T. urticae in glass slide-dipping assay and had significant mite control effects in a pot experiment, but required a high concentration to achieve similar control effects to spirodiclofen. The toxicity evaluation suggested that compound No. 8 had no acute toxicity on pollinator honey bees and natural predator N. californicus and did not affect strawberry growth in our assay. Compound No. 8 is a potential lead compound for developing novel acaricides with reduced nontarget toxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae)

Wang

Cao

Lai

et al. 2023

Journal of Insect Science

View full text Add to dashboard Cite

show abstract

“…The activity of these compounds was also evaluated on acetylcholinesterase, which is responsible in terrestrial invertebrates for various primordial biosynthetic pathways, the inhibition of which can be lethal for insect species and thus represents a great phytosanitary interest [44,45], and also might be a toxicity indicator in the marine environment, especially in bivalves [46].…”

Section: Acetylcholinesterase Activity Inhibitionmentioning

confidence: 99%

Bioactive Bromotyrosine Derivatives from the Pacific Marine Sponge Suberea clavata (Pulitzer-Finali, 1982)

et al. 2021

View full text Add to dashboard Cite

Chemical investigation of the South-Pacific marine sponge Suberea clavata led to the isolation of eight new bromotyrosine metabolites named subereins 1–8 (2–9) along with twelve known co-isolated congeners. The detailed configuration determination of the first representative major compound of this family 11-epi-fistularin-3 (11R,17S) (1) is described. Their chemical characterization was achieved by HRMS and integrated 1D and 2D NMR (nuclear magnetic resonance) spectroscopic studies and extensive comparison with literature data. For the first time, a complete assignment of the absolute configurations for stereogenic centers C-11/17 of the known members (11R,17S) 11-epi-fistularin-3 (1) and 17-deoxyfistularin-3 (10) was determined by a combination of chemical modifications, Mosher’s technology, and ECD spectroscopy. Consequently, the absolute configurations of all our new isolated compounds 2–9 were determined by the combination of NMR, Mosher’s method, ECD comparison, and chemical modifications. Interestingly, compounds 2–7 were obtained by chemical transformation of the major compound 11-epi-fistularin-3 (1). Evaluation for acetylcholinesterase inhibition (AChE), DNA methyltransferase 1 (DNMT1) modulating activity and antifouling activities using marine bacterial strains are also presented.

show abstract

“…Efforts have been made to formulate new insecticides with the objective of diminishing off-target toxicity and minimizing the resistance associated with AChE inhibitors. ,, One approach involves targeting the insect-specific cysteine residue of AChE . On the basis of the insect-specific cysteine residue, a series of novel AChE inhibitors have been developed that exhibit enhanced efficacy against insect AChE compared to that of mammals. − However, these inhibitors are not effective for the management of species devoid of pest-specific cysteine residues within AChE, such as members of Arachnida, including mites and ticks . To overcome this resistance issue, several studies have focused on the development of AChE inhibitors used to control resistant mosquitoes by targeting Ag AChE containing the G119S mutation.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Inhibitor of Cimex lectularius Acetylcholinesterase

Qin,

Yuchi

2024

J. Agric. Food Chem.

View full text Add to dashboard Cite

Acetylcholinesterase (AChE) stands as a primary target of commercial insecticides, notably organophosphates and carbamates. Despite their widespread use in agricultural and indoor pest control, concerns over their high toxicity and the emergence of resistance have restricted their efficacy. In this study, we conducted high-throughput virtual screening against both wild-type (WT) and resistant Cimex lectularius AChE utilizing a library encompassing 1 270 000 compounds. From this screening, we identified 100 candidate compounds and subsequently assessed their inhibitory effects on purified AChE enzymes. Among these candidates, AE027 emerged as a potent inhibitor against both WT and resistant AChE, exhibiting IC50 values of 10 and 43 μM, respectively. Moreover, the binding of AE027 significantly stabilized AChE, elevating its melting temperature by approximately 7 °C. Through molecular docking and molecular dynamics simulation, we delineated the binding mode of AE027, revealing its interaction with a site adjacent to the catalytic center, which is distinct from known inhibitors, with differing poses observed between WT and resistant AChE. Notably, the resistance mutation F348Y, positioned at a site directly interfacing with AE027, impedes ligand binding through steric hindrance. Furthermore, we evaluated the toxicity and pharmacokinetic properties of AE027 utilizing bioinformatics tools. These findings lay a crucial foundation for the development of a novel generation of insecticides that can combat both WT and resistant pest populations effectively and safely.

show abstract

The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening

Cited by 11 publications

References 108 publications

Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae)

Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae)

Bioactive Bromotyrosine Derivatives from the Pacific Marine Sponge Suberea clavata (Pulitzer-Finali, 1982)

Identification of a Novel Inhibitor of Cimex lectularius Acetylcholinesterase

Contact Info

Product

Resources

About