Acute Toxicity of Organophosphorus Compounds

Morris, Christopher M.; Savy, Claire Y.; Judge, Sarah J.; Blain, Peter G.

doi:10.1007/978-1-4471-5625-3_3

Cited by 12 publications

(7 citation statements)

References 185 publications

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“…48 The largest class of acute oral toxic compounds are organophosphorus compounds, with 372 structural representatives in the data set. These compounds are known inhibitors of acetylcholinesterase (AChE) 49,50 and are widely used in agriculture as insecticides, with compounds like fosmethilan (1) as a well-known representative. The second cluster of acute oral toxic compounds shares the 2trifluoromethylbenzimidazole partial structure, which is found in 128 compounds in the data set.…”

Section: ■ Resultsmentioning

confidence: 99%

In Silico Prediction of Oral Acute Rodent Toxicity Using Consensus Machine Learning

Schieferdecker,

Rottach,

Vock

2024

J. Chem. Inf. Model.

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Acute oral toxicity (AOT) is required for the classification and labeling of chemicals according to the global harmonized system (GHS). Acute oral toxicity studies are optimized to minimize the use of animals. However, with the advent of the three R s principles and machine learning in toxicology, alternative in silico methods became a reasonable alternative approach for addressing the AOT of new chemical matter. Here, we describe the compilation of AOT data from a commercial database and the development of a consensus classification model after evaluating different combinations of molecular representations and machine learning algorithms. The model shows significantly better performance compared to publicly available AOT models. Its performance was evaluated on an external validation data set, which was compiled from the literature, and an applicability domain was deduced.

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Section: ■ Resultsmentioning

confidence: 99%

In Silico Prediction of Oral Acute Rodent Toxicity Using Consensus Machine Learning

Schieferdecker,

Rottach,

Vock

2024

J. Chem. Inf. Model.

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“…In comparison to existing AChE-targeting insecticides, AE027 showed greater pest selectivity as well as better resistance-breaking properties. OPs are notorious for their high toxicity as a result of their ability to non-selectively irreversibly inhibit AChEs from different species by forming covalent bonds with catalytic serine residues, resulting in the accumulation of acetylcholine and subsequent overstimulation of the nervous system. − AE027 inhibits AChE via safe non-covalent interactions. Furthermore, in comparison to CB insecticides, AE027 also showed better selectivity against the pest AChE, as proven by the docking scores.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Inhibitor of Cimex lectularius Acetylcholinesterase

Qin,

Yuchi

2024

J. Agric. Food Chem.

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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.

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“…rganophosphorus (OP) compounds have vigorous anticholinesterase activity and are commonly used as insecticides and pesticides [1]. OP poisoning is a global health problem due to occupational, accidental, or intentional exposure (to commit suicide), especially in developing countries, and poses a threat to human health [2].…”

Section: Introductionmentioning

confidence: 99%

Severe Accidental Organophosphorus Poisoning in Two Children

Aminisefat

Saravani

2020

IJMTFM

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Background: Organophosphorus (OP) compounds have intense anticholinesterase activity and are commonly used as insecticides and pesticides. OP poisoning is a global health problem and poses a threat to human health. Case Report: Here we report two sisters, aged 3 and 4 years, who had inadvertently eaten agricultural pesticides. These patients had a decreased level of consciousness, nausea, and vomiting. We do not have pralidoxime in this center and the adjacent center, so we used atropine as the primary drug in treating these patients. However, after 4 days, the 3-year-old patient felt a weakness in upper and lower limb movements. Conclusion: In the treatment of OP poisoning, it is necessary to pay special attention to delayed complications such as intermediate syndrome.

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Acute Toxicity of Organophosphorus Compounds

Cited by 12 publications

References 185 publications

In Silico Prediction of Oral Acute Rodent Toxicity Using Consensus Machine Learning

In Silico Prediction of Oral Acute Rodent Toxicity Using Consensus Machine Learning

Identification of a Novel Inhibitor of Cimex lectularius Acetylcholinesterase

Severe Accidental Organophosphorus Poisoning in Two Children

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