The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro
Abstract
:1. Introduction
2. Results and Discussion
2.1. The Conformational Analysis of Pesticides in Aqueous Solution
2.2. The Prediction of Pesticides Structures in Aqueous Solution
2.3. The Prediction of Externally Evaluated Pesticides Structures in Aqueous Solution
2.4. The Pesticides Acute Toxicity Anticipation through the Pre-Bound Conformations
2.5. The Structure-Based Studies
2.5.1. The Alignment Rules Assessment
2.5.2. The Cross-Docking and Molecular Dynamics Studies of ACh
2.5.3. The Cross-Docking and Molecular Dynamics Studies of Pesticides 2-chloro-1,3,5-triazine Group
2.5.4. The Cross-Docking and Molecular Dynamics Studies of Pesticides Amide Group
2.5.5. The Cross-Docking and Molecular Dynamics Studies of Pesticides (6-Chloropyridin-3-Yl)Methanamine and 1-(4-Chlorophenyl)-3-methylurea Groups
2.5.6. The Cross-Docking of Externally Evaluated Pesticides
2.6. The Pesticides Acute Toxicity Anticipation through the Bioactive Conformations
2.7. The Quantum Mechanical Studies of Acetylcholinesterase Inhibition by 2-Chloro-1,3,5-triazine-based Pesticides
2.8. The Concentration-Dependent Kinetics of Human Acetylcholinesterase Inhibition by 2-Chloro-1,3,5-triazine-based Pesticides
3. Materials and Methods
3.1. Materials
3.2. The Generation of Pesticides Structures
3.3. The Conformational Analysis
3.4. The Mus musculus and Homo sapiens AChE Sequences Alignment
3.5. The Mus musculus and Homo sapiens AChE Complexes Preparation
3.6. The Structure-Based Alignment Assessment
3.6.1. The AutoDock Settings
3.6.2. The Autodock Vina Settings
3.6.3. The DOCK6 Settings
3.7. The Ligand-Based and Structure-Based Alignment Accuracy
3.8. The Structure-Based Alignment of Pesticides
3.9. The Pesticide-AChE Complexes Molecular Dynamics Simulations
3.10. The MM-GBSA Calculations and Free Energy Decomposition
3.11. The Quantum Mechanical Mechanistic Studies
3.12. The Assay of the AChE Activity
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Pesticide | Structure | LD50 (mg/kg) | Ref. | Pesticide | Structure | LD50 (mg/kg) | Ref. |
---|---|---|---|---|---|---|---|
atrazine | 0.850 0.0689 | [20] | tebufenozide | 5000 405.40 | [29] | ||
propazine | 3.18 0.258 | [21] | imidacloprid | 131 10.62 | [30] | ||
simazine | 5 0.405 | [24] | acetamiprid | 18 14.92 | [31] | ||
carbofuran | 2 0.162 | [25] | diuron | 500 40.54 | [22] | ||
monocrotophos | 14 1.135 | [26] | monuron | 1700 437.84 | [23] | ||
dimethoate | 60 4.86 | [27] | linuron | 2400 194.59 | [19] | ||
carbaryl | 100 8.11 | [28] | acetylcholine |
Pesticide | Structure | LD50 (mg/kg) | Ref. | Pesticide | Structure | LD50 (mg/kg) | Ref. |
---|---|---|---|---|---|---|---|
azamethiphos | 1040 84.324 | [44] | phosmet | 113 9.162 | [53] | ||
azinphos-methyl | 7 0.567 | [54] | TCVP | 465 37.702 | [55] | ||
chlorpyrifos | 2000 162.162 | [56] | terbufos | 1.6 0.129 | [57] | ||
DDVP | 17 1.378 | [58] | methiocarb | 350 28.378 | [59] | ||
diazinon | 66 5.351 | [60] | methomyl | 12 0.972 | [61] | ||
fenitrothion | 50 40.540 | [62] | oxamyl | 5.4 0.437 | [63] | ||
glyphosate | 5000 405.405 | [64] | DDT | 113 9.162 | [14] | ||
malathion | 290 23.513 | [65] | 2,4-D | 639 51.810 | [66] | ||
methyl parathion | 18 1.459 | [67] | dicamba | 75 61.378 | [68] | ||
naled (dibrom) | 160 12.972 | [69] | DEET | 1.95 0.158 | [70] | ||
parathion | 2 0.162 | [71] | sulfoxaflor | 750 60.810 | [72] |
Pesticide | FF a | Eglob_minb | NGMS c | NF d | Pesticide | CAA f |
---|---|---|---|---|---|---|
(kJ/mol) | Alignment e | RMSD (Å) g | ||||
simazine | MM3 | NA h | NA | NA | EC/MMFF | |
AMBER94 | NA | NA | NA | 0.667 | ||
MMFF | −1022.18 | 136 | 2782 | |||
MMFFs | NA | NA | NA | |||
OPLSAA | −793.61 | 158 | 2306 | |||
monocrotophos | MM3 | NA | NA | NA | EC/MMFF | |
AMBER94 | NA | NA | NA | 0.620 | ||
MMFF | −307.36 | 241 | 62 | EC/MMFFs | ||
MMFFs | −310.26 | 218 | 61 | 3.521 | ||
OPLSAA | NA | NA | NA | |||
dimethoate | MM3 | NA | NA | NA | EC/MMFF | |
AMBER94 | NA | NA | NA | 0.148 | ||
MMFF | −383.68 | 340 | 44 | EC/MMFFs | ||
MMFFs | −386.71 | 215 | 40 | 3.227 | ||
OPLSAA | −228.66 | 998 | 15 | EC/OPLSAA | ||
2.746 | ||||||
acetamiprid | MM3 | NA | NA | NA | EC/MMFF | |
AMBER94 | NA | NA | NA | 0.783 | ||
MMFF | −31.45 | 1916 | 14 | EC/MMFFs | ||
MMFFs | −31.29 | 1816 | 6 | 0.823 | ||
OPLSAA | NA | NA | NA |
Pesticide | FF a | Eglob_min b | NGMS c | NF d | Pesticide | FFDAA f |
---|---|---|---|---|---|---|
(kJ/mol) | Alignment e | RMSD (Å) g | ||||
atrazine | MM3 | −1161.48 | 445 | 23 | MM3/MMFF | |
AMBER94 | NA h | NA | NA | 0.892 | ||
MMFF | −1007.32 | 147 | 62 | MM3/MMFFs | ||
MMFFs | −992.63 | 509 | 20 | 0.931 | ||
OPLSAA | −783.57 | 364 | 19 | MMFF/MMFFS | ||
0.343 | ||||||
carbofuran | MM3 | 29.60 | 3617 | 2 | MMFF/MMFFS | |
AMBER94 | NA | NA | NA | 0.075 | ||
MMFF | 20.30 | 3307 | 2 | MMFF/OPLSAA | ||
MMFFs | 15.92 | 3384 | 2 | 0.216 | ||
OPLSAA | 73.27 | 5621 | 75 | MMFFs/OPLSAA | ||
0.239 |
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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. https://doi.org/10.3390/molecules23092192
Mladenović M, Arsić BB, Stanković N, Mihović N, Ragno R, Regan A, Milićević JS, Trtić-Petrović TM, 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(9):2192. https://doi.org/10.3390/molecules23092192
Chicago/Turabian StyleMladenović, Milan, Biljana B. Arsić, Nevena Stanković, Nezrina Mihović, Rino Ragno, Andrew Regan, Jelena S. Milićević, Tatjana M. Trtić-Petrović, and Ružica Micić. 2018. "The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro" Molecules 23, no. 9: 2192. https://doi.org/10.3390/molecules23092192
APA StyleMladenović, M., Arsić, B. B., Stanković, N., Mihović, N., Ragno, R., Regan, A., Milićević, J. S., Trtić-Petrović, T. M., & Micić, R. (2018). The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro. Molecules, 23(9), 2192. https://doi.org/10.3390/molecules23092192