The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro

Abstract

Commercially available pesticides were examined as Mus musculus and Homo sapiens acetylcholinesterase (mAChE and hAChE) inhibitors by means of ligand-based (LB) and structure-based (SB) in silico approaches. Initially, the crystal structures of simazine, monocrotophos, dimethoate, and acetamiprid were reproduced using various force fields. Subsequently, LB alignment rules were assessed and applied to determine the inter synaptic conformations of atrazine, propazine, carbofuran, carbaryl, tebufenozide, imidacloprid, diuron, monuron, and linuron. Afterwards, molecular docking and dynamics SB studies were performed on either mAChE or hAChE, to predict the listed pesticides’ binding modes. Calculated energies of global minima (Eglob_min) and free energies of binding (∆Gbinding) were correlated with the pesticides’ acute toxicities (i.e., the LD50 values) against mice, as well to generate the model that could predict the LD50s against humans. Although for most of the pesticides the low Eglob_min correlates with the high acute toxicity, it is the ∆Gbinding that conditions the LD50 values for all the evaluated pesticides. Derived pLD50 = f(∆Gbinding) mAChE model may predict the pLD50 against hAChE, too. The hAChE inhibition by atrazine, propazine, and simazine (the most toxic pesticides) was elucidated by SB quantum mechanics (QM) DFT mechanistic and concentration-dependent kinetic studies, enriching the knowledge for design of less toxic pesticides.

Exposição aos defensores agrícolas: Norteadores fisiopatológicos sistêmicos a partir dos receptores colinérgicos muscarínicos e nicotínicos

“…Embora os efeitos tóxicos dos agrotóxicos sejam bem conhecidos, relativamente pouco se sabe sobre as implicações bioquímicas e fisiológicas de pesticidas que atuam como inibidores da AChE (Mladenović et al, 2018). O mecanismo de ação se valida pela ligação dos agroquímicos a enzima acetilcolinesterase (AChE), podendo ser de maneira reservivel ou irreversível, a depender da classe dos agrotóxicos (Mello, Silva, 2013;Gutiérrez et al, 2015).…”

“…A partir desse ponto, os mecanismos fisiopatológicos se explicam pela estimulação constante dos receptores muscarinicos do sistema nervoso parassimpático autônomo e dos receptores nicotínicos, trazendo consequências sistêmicas importantes (Mladenović et al, 2018). A ativação dos referidos receptores, acoplados a proteína G, resultam na abertura de canais iônicos e ativação do monofostato de adenosina cíclico (AMPc) ou monofosfato der guanosina cíclica (GMPc), na célula neuronal (Hall & Guyton, 2017).…”

Rapid detection of pesticide in milk, cereal and cereal based food and fruit juices using paper strip-based sensor

“…Pesticide is the toxic chemical can inhibit the acetyl cholinesterase enzyme system in eukaryotic cells that degrade neurotransmitter acetylcholine into acetate and choline in central nervous system of human, pest and rodents. Over exposure of pesticide cause increase in concentration of acetylcholine in brain and blood which has harmful effect to host 14 . IN case of prokaryotic microorganisms like Bacillus megaterium are associated with the cell bound esterase 15 .…”

Violation of Local Immunity of the Oral Cavity in Agro-Industrial Workers with Generalized Periodontitis under the Influence of Pesticides

“…За джерелами літератури вітчизняних та закордонних авторів, в умовах сучасного агропромислового виробництва, на організм працюючих впливає комплекс шкідливих стимулів: хімічні речовини, вібрація, шум, температура, підвищена вологість, тощо. Названі фактори призводять до напруження адаптивних та захисно-компенсаторних механізмів [12,13,14].…”