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Open AccessFeature PaperArticle

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

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Kragujevac Center for Computational Biochemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, P.O. Box 60, 34000 Kragujevac, Serbia
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Department of Mathematics, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia
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Division of Pharmacy and Optometry, University of Manchester, Oxford Road, Manchester M13 9PT, UK
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Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Faculty of Pharmacy and Medicine, Sapienza Rome University, P.le A. Moro 5, 00185 Rome, Italy
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Alchemical Dynamics srl, 00125 Rome, Italy
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School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
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Vinča Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
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Faculty of Sciences and Mathematics, University of Priština, Lole Ribara 29, 38220 Kosovska Mitrovica, Serbia
*
Author to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Molecules 2018, 23(9), 2192; https://doi.org/10.3390/molecules23092192
Received: 6 August 2018 / Revised: 24 August 2018 / Accepted: 24 August 2018 / Published: 30 August 2018
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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. View Full-Text
Keywords: pesticides; AChE; conformational analysis; QSAR; molecular docking; molecular dynamics; quantum-chemical studies; concentration-dependent kinetic studies pesticides; AChE; conformational analysis; QSAR; molecular docking; molecular dynamics; quantum-chemical studies; concentration-dependent kinetic studies
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MDPI and ACS Style

Mladenović, M.; Arsić, B.B.; Stanković, N.; Mihović, N.; Ragno, R.; Regan, A.; Milićević, J.S.; Trtić-Petrović, T.M.; Micić, R. The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro. Molecules 2018, 23, 2192.

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