Investigate the binding of pesticides with the TLR4 receptor protein found in mammals and zebrafish using molecular docking and molecular dynamics simulations.
3FXI
Cardiovascular toxicity
Molecular docking
Molecular dynamics simulations
Pesticides
Toll-like receptor 4 (TLR4)
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
received:
08
07
2024
accepted:
07
10
2024
medline:
19
10
2024
pubmed:
19
10
2024
entrez:
18
10
2024
Statut:
epublish
Résumé
The widespread use of pesticides poses significant threats to both environmental and human health, primarily due to their potential toxic effects. The study investigated the cardiovascular toxicity of selected pesticides, focusing on their interactions with Toll-like receptor 4 (TLR4), an important part of the innate immune system. Using computational tools such as molecular docking, molecular dynamics (MD) simulations, principal component analysis (PCA), density functional theory (DFT) calculations, and ADME analysis, this study identified C160 as having the lowest binding affinity (-8.2 kcal/mol), followed by C107 and C165 (-8.0 kcal/mol). RMSD, RMSF, Rg, and hydrogen bond metrics indicated the formation of stable complexes between specific pesticides and TLR4. PCA revealed significant structural changes upon ligand binding, affecting stability and flexibility, while DFT calculations provided information about the stability, reactivity, and polarity of the compounds. ADME studies highlighted the solubility, permeability, and metabolic stability of C107, C160, and C165, suggesting their potential for bioavailability and impact on cardiovascular toxicity. C107 and C165 exhibit higher bioactivity scores, indicating favourable absorption, metabolism, and distribution properties. C165 also violated rule where molecular weight is greater than 500 g/mol. Further, DFT and NCI analysis of post MD conformations confirmed the binding of ligands at the binding pocket. The analysis shed light on the molecular mechanisms of pesticide-induced cardiovascular toxicity, aiding in the development of strategies to mitigate their harmful effects on human health.
Identifiants
pubmed: 39424974
doi: 10.1038/s41598-024-75527-6
pii: 10.1038/s41598-024-75527-6
doi:
Substances chimiques
Toll-Like Receptor 4
0
Pesticides
0
Ligands
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
24504Informations de copyright
© 2024. The Author(s).
Références
Tudi, M. et al. Agriculture development, pesticide application and its impact on the environment. Int. J. Environ. Res. Public. Health. 18, 1112 (2021).
pubmed: 33513796
pmcid: 7908628
doi: 10.3390/ijerph18031112
Rani, L. et al. An extensive review on the consequences of chemical pesticides on human health and environment. J. Clean. Prod. 283, 124657 (2021).
doi: 10.1016/j.jclepro.2020.124657
Vellingiri, B. et al. Neurotoxicity of pesticides – A link to neurodegeneration. Ecotoxicol. Environ. Saf. 243, 113972 (2022).
pubmed: 36029574
doi: 10.1016/j.ecoenv.2022.113972
El-Nahhal, Y. & El-Nahhal, I. Cardiotoxicity of some pesticides and their amelioration. Environ. Sci. Pollution Res. 2021. 28:33 (28), 44726–44754 (2021).
doi: 10.1007/s11356-021-14999-9
Sánchez-Alarcón, J. et al. A systematic review of studies on genotoxicity and related biomarkers in populations exposed to pesticides in Mexico. Toxics 2021. 9, 272 (2021).
de Teixeira, J. R. Embryotoxic effects of pesticides in zebrafish (Danio rerio): Diflubenzuron, pyriproxyfen, and its mixtures. Toxics. 12, 160 (2024).
pubmed: 38393255
pmcid: 10892354
doi: 10.3390/toxics12020160
Zago, A. M. et al. Global Public Health Pesticide exposure and risk of cardiovascular disease: A systematic review. (2020). https://doi.org/10.1080/17441692.2020.1808693
Le Quilliec, E., Fundere, A., Al-U’datt, D. G. F. & Hiram, R. Pollutants, including organophosphorus and organochloride pesticides, may increase the risk of cardiac remodeling and atrial fibrillation: a narrative review. Biomedicines. 11, 2427 (2023).
Sampurna, B. P. et al. Cardiac rhythm and molecular docking studies of ion channel ligands with cardiotoxicity in zebrafish. Cells 2019. 8, 566 (2019).
Wu, Y. et al. Developmental toxicity, immunotoxicity and cardiotoxicity induced by methidathion in early life stages of zebrafish. Pestic Biochem. Physiol. 194, 105526 (2023).
pubmed: 37532338
doi: 10.1016/j.pestbp.2023.105526
Saputra, F. et al. The effect of the pyrethroid pesticide fenpropathrin on the cardiac performance of zebrafish and the potential mechanism of toxicity. Biology (Basel). 12, 1214 (2023).
pubmed: 37759613
Peri, F. & Piazza, M. Therapeutic targeting of innate immunity with toll-like receptor 4 (TLR4) antagonists. Biotechnol. Adv. 30, 251–260 (2012).
pubmed: 21664961
doi: 10.1016/j.biotechadv.2011.05.014
Gawali, B., Sridharan, V., Krager, K. J., Boerma, M. & Pawar, S. A. TLR4—A Pertinent Player in Radiation-Induced Heart Disease? Genes 14, 1002 (2023).
Gu, J., Guo, L., Hu, J., Ji, G. & Yin, D. Potential adverse outcome pathway (AOP) of emamectin benzoate mediated cardiovascular toxicity in zebrafish larvae (Danio rerio). Sci. Total Environ. 900, 165787 (2023).
pubmed: 37499828
doi: 10.1016/j.scitotenv.2023.165787
Honegr, J. et al. Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro. Eur. J. Med. Chem. 146, 38–46 (2018).
pubmed: 29407964
doi: 10.1016/j.ejmech.2017.12.074
Honegr, J. et al. Rational design of a new class of toll-like receptor 4 (TLR4) tryptamine related agonists by means of the structure- and ligand-based virtual screening for vaccine adjuvant discovery. Molecules 23 (2018). https://doi.org/10.3390/molecules23010102
Murgueitio, M. S. et al. Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2). Biochim. Biophys. Acta (BBA) Gen. Subj. 1861, 2680–2689 (2017).
Farhadi, T., Ovchinnikov, R. S. & Ranjbar, M. M. In silico designing of some agonists of toll-like receptor 5 as a novel vaccine adjuvant candidates. Netw. Model. Anal. Health Inf. Bioinf. 5, 31 (2016).
doi: 10.1007/s13721-016-0138-1
Švajger, U. et al. Novel toll-like receptor 4 (TLR4) antagonists identified by structure- and ligand-based virtual screening. Eur. J. Med. Chem. 70, 393–399 (2013).
pubmed: 24177366
doi: 10.1016/j.ejmech.2013.10.019
Smith, M. et al. Trial Watch: Toll-like receptor agonists in cancer immunotherapy. OncoImmunology 7 (2018). https://doi.org/10.1080/2162402X.2018.1526250
Alderson, M. R., McGowan, P., Baldridge, J. R. & Probst, P. TLR4 agonists as immunomodulatory agents. J. Endotoxin Res. 12, 313-319 (2006).
Shafaghi, M. et al. Immunoinformatics-aided design of a new multi-epitope vaccine adjuvanted with domain 4 of pneumolysin against Streptococcus pneumoniae strains. BMC Bioinform. 24, 67 (2023).
Chen, N. Y., Li, C. P. & Huang, H. F. Synthesis, antitumor evaluation and computational study of thiazolidinone derivatives of dehydroabietic acid-based B ring-fused-thiazole. Mol. Divers. 28, 875-888 (2024).
Ikenohuchi, Y. J. et al. A C-type lectin induces NLRP3 inflammasome activation via TLR4 interaction in human peripheral blood mononuclear cells. Cell. Mol. Life Sci. 80, 188 (2023).
Pérez-Regidor, L. et al. Small molecules as toll-like receptor 4 modulators drug and in-house computational repurposing. Biomedicines 10, (2022).
Anwar, M. A., Panneerselvam, S., Shah, M. & Choi, S. Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid a detection. Sci. Rep. 5, 7657 (2015).
de Oliveira, A. A., Faustino, J., de Lima, M. E., Menezes, R. & Nunes, K. P. Unveiling the interplay between the TLR4/MD2 complex and HSP70 in the human cardiovascular system: a computational approach. Int. J. Mol. Sci. 20, 3121 (2019).
Vila-Casahonda, R. G., Lozano-Aponte, J. & Guerrero-Beltrán, C. E. HSP60-Derived peptide as an LPS/TLR4 modulator: an in silico approach. Front. Cardiovasc. Med. 9, 731376 (2022).
Pence, H. E. & Williams, A. ChemSpider: an Online Chemical Information Resource. J. Chem. Educ. 87, 1123–1124 (2010).
doi: 10.1021/ed100697w
Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009).
pubmed: 19399780
pmcid: 2760638
doi: 10.1002/jcc.21256
Baroroh, S., Muscifa, U., Destiarani, Z. S., Rohmatullah, W., Yusuf, M. & F. G. & Molecular interaction analysis and visualization of protein-ligand docking using Biovia Discovery Studio Visualizer. Indones. J. Comput. Biol. (IJCB). 2, 22 (2023).
doi: 10.24198/ijcb.v2i1.46322
Patil, S., Patil, A., Molecular Docking, P. & V. &, A useful approach of Drug Discovery on the basis of their structure. Asian J. Pharm. Res. 191–195. https://doi.org/10.52711/2231-5691.2023.00036 (2023).
Benjamin, I. et al. Antimalarial potential of naphthalene-sulfonic acid derivatives: molecular electronic properties, vibrational assignments, and in-silico molecular docking studies. J. Mol. Struct. 1264, 133298 (2022).
doi: 10.1016/j.molstruc.2022.133298
Yadav, S. et al. Analytic and in Silico methods to understand the interactions between Dinotefuran and Haemoglobin. Chem. Biodivers. e202400495 https://doi.org/10.1002/CBDV.202400495 (2024).
Raman, A. P. S. et al. In silico evaluation of binding of 2-deoxy-D-glucose with Mpro of nCoV to Combat COVID-19. Pharm. 2022. 14, 135 (2022).
Singh, M. B. et al. A comparative study of 5- fluorouracil, doxorubicin, methotrexate, paclitaxel for their inhibition ability for Mpro of nCoV: molecular docking and molecular dynamics simulations. J. Indian Chem. Soc. 99, 100790 (2022).
doi: 10.1016/j.jics.2022.100790
Vishvakarma, V. K. et al. Pyrrolothiazolones as potential inhibitors for the nsP2B-nsP3 protease of Dengue Virus and their mechanism of synthesis. ChemistrySelect. 4, 9410–9419 (2019).
doi: 10.1002/slct.201901119
Kumar, D. et al. Understanding the binding affinity of noscapines with protease of SARS-CoV-2 for COVID-19 using MD simulations at different temperatures. J. Biomol. Struct. Dyn. 39, 2659–2672 (2021).
pubmed: 32362235
doi: 10.1080/07391102.2020.1752310
Babu Singh, M. et al. An in Silico investigation for acyclovir and its derivatives to fight the COVID-19: molecular docking, DFT calculations, ADME and td-molecular dynamics simulations. J. Indian Chem. Soc. 99, 100433 (2022).
doi: 10.1016/j.jics.2022.100433
Shukla, R. & Tripathi, T. Molecular dynamics simulation of protein and protein-ligand complexes. Comput. Aided Drug Des. 133–161. https://doi.org/10.1007/978-981-15-6815-2_7/FIGURES/8 (2020).
Alka, Vishvakarma, V. K., Yadav, S., Singh, P. & Jain, P. In vitro, in silico, ADME and theoretical analysis of Mn(II) and Co(II) complexes derived from methyl-(Z)-N′-carbamothioylcarbamohydrazonate Schiff Base ligand. Chem Biodivers 20, e202300042 (2023).
Radwan, H. A. et al. Design, synthesis, in vitro anticancer and antimicrobial evaluation, SAR analysis, molecular docking and dynamic simulation of new pyrazoles, triazoles and pyridazines based isoxazole. J. Mol. Struct. 1264, 133312 (2022).
doi: 10.1016/j.molstruc.2022.133312
Rani, A. et al. Computational insights into chromene/pyran derivatives: Molecular docking, ADMET studies, DFT calculations, and MD simulations as promising candidates for Parkinson’s disease. Chem. Biodivers. e202400920 https://doi.org/10.1002/CBDV.202400920 (2024).
Singh Babu, M. et al. In silico study for acyclovir and its derivatives against Mpro of nCoV: Temperature dependent molecular dynamics simulations (2022). https://doi.org/10.21203/RS.3.RS-1250241/V1
Gheidari, D., Mehrdad, M. & Bayat, M. Synthesis, docking, MD simulation, ADMET, drug likeness, and DFT studies of novel furo[2,3-b]indol-3a-ol as promising Cyclin-dependent kinase 2 inhibitors. Sci. Rep. 2024 14:1 14, 1–16 (2024).
Haider, S., Barakat, A. & Ul-Haq, Z. Discovery of potential chemical probe as inhibitors of CXCL12 using ligand-based virtual screening and Molecular Dynamic Simulation. Molecules 25, 4829 (2020).
pubmed: 33092204
pmcid: 7594044
doi: 10.3390/molecules25204829
Hendam, A., Al-Sadek, A. F. & Hefny, H. A. Molecular dynamic simulation of Neurexin1α mutations associated with mental disorder. J. Mol. Neurosci. 72, 2252–2272 (2022).
pubmed: 36197641
pmcid: 9532826
doi: 10.1007/s12031-022-02072-0
Anjum, F. et al. Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics. RSC Adv. 12, 7872–7882 (2022).
pubmed: 35424745
pmcid: 8982221
doi: 10.1039/D1RA09339H
Kumari, A., Mittal, L., Srivastava, M., Pathak, D. P. & Asthana, S. Conformational characterization of the Co-activator binding site revealed the mechanism to achieve the bioactive state of FXR. Front. Mol. Biosci. 8, 658312 (2021).
Abu-Dief, A. M. et al. Synthesize, structural inspection, stoichiometry in solution and DFT calculation of some novel mixed ligand complexes: DNA binding, biomedical applications and molecular docking approach. J. Mol. Liq. 399, 124422 (2024).
doi: 10.1016/j.molliq.2024.124422
Raman, A. P. S. et al. Exploring the molecular interactions between acyclovir and hormones: insights from density functional theory calculations. ChemistrySelect 8, e202303320 (2023).
Abu-Izneid, T. et al. Density functional theory (DFT), molecular docking, and xanthine oxidase inhibitory studies of dinaphthodiospyrol S from Diospyros kaki L. Saudi Pharm. J. 32, 101936 (2024).
pubmed: 38261938
doi: 10.1016/j.jsps.2023.101936
Raman, A. P. S. et al. DFT calculations, molecular docking and SAR investigation for the formation of eutectic mixture using thiourea and salicylic acid. J. Mol. Liq. 362, 119650 (2022).
doi: 10.1016/j.molliq.2022.119650
Moyeenul Huq, A. K. M. et al. Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation. PLoS One. 19, e0299238 (2024).
doi: 10.1371/journal.pone.0299238
Quayum, S. T. et al. Exploring the effectiveness of flavone derivatives for treating liver diseases: utilizing DFT, molecular docking, and molecular dynamics techniques. MethodsX. 12, 102537 (2024).
pubmed: 38299040
doi: 10.1016/j.mex.2023.102537
Smith, D. A., Beaumont, K., Maurer, T. S. & Di, L. Clearance in drug design. J. Med. Chem. 62, 2245–2255 (2019).
pubmed: 30281973
doi: 10.1021/acs.jmedchem.8b01263
Yousaf, M. A., Basheera, S. & Sivanandan, S. Inhibition of Monkeypox Virus DNA polymerase using Moringa oleifera Phytochemicals: computational studies of drug-Likeness, molecular docking, molecular dynamics simulation and density functional theory. Indian J. Microbiol. 1–18. https://doi.org/10.1007/S12088-024-01244-3/FIGURES/5 (2024).
Aslam, M. et al. Study the solubility of pharmaceutical ingredients and their eutectic mixtures: an in-depth density functional theory and molecular dynamics simulations approaches. J. Mol. Liq. 397, 124070 (2024).
doi: 10.1016/j.molliq.2024.124070
Singh, H., Singh, A., Banipal, T. S., Singh, P. & Bahadur, I. Temperature and concentration dependent physicochemical interactions of L-ascorbic acid in aqueous LiCl solution: experimental and theoretical study. Colloids Surf. Physicochem. Eng. Asp. 623, 126672 (2021).
doi: 10.1016/j.colsurfa.2021.126672
Saouli, S. et al. Synthesis, spectroscopic characterization, crystal structure, DFT studies and biological activities of new hydrazone derivative: 1-(2,5-bis((E)-4-isopropylbenzylidene)cyclopentylidene)-2-(2,4-dinitrophenyl) hydrazine. J. Mol. Struct. 1213, 128203 (2020).
doi: 10.1016/j.molstruc.2020.128203
Zouchoune, B. Theoretical investigation on the biological activities of ginger and some of its combinations: an overview of the antioxidant activity. Struct. Chem. 32, 1659–1672 (2021).
doi: 10.1007/s11224-021-01725-x
Allal, H., Nemdili, H., Zerizer, M. A. & Zouchoune, B. Molecular structures, chemical descriptors, and pancreatic lipase (1LPB) inhibition by natural products: a DFT investigation and molecular docking prediction. Struct. Chem. 35, 223–239 (2024).
doi: 10.1007/s11224-023-02176-2
Kumar, A., Kumari, K., Singh, S., Bahdur, I. & Singh, P. Noscapine anticancer drug designed with ionic liquids to enhance solubility: DFT and ADME approach. J. Mol. Liq. 325, 115159 (2021).
doi: 10.1016/j.molliq.2020.115159
Kumar, A. et al. Promising iron(II) complexes of curcumins: designing, density functional theory, and molecular docking. J. Phys. Org. Chem. 34, e4196 (2021).
doi: 10.1002/poc.4196
Aslam, M. et al. Impact of functional group positioning in the anion of ionic liquids on aqueous solubility: a study through DFT calculations. Ionics (Kiel). 30, 875–887 (2024).
doi: 10.1007/s11581-023-05305-3
Abu-Melha, S. et al. Multicomponent synthesis, DFT calculations and molecular docking studies of novel thiazolyl-pyridazinones as potential antimicrobial agents against antibiotic-resistant bacteria. J. Mol. Struct. 1234, 130180 (2021).
doi: 10.1016/j.molstruc.2021.130180
Yadav, S. et al. Insights into DES Stability and reactivity with carboxylic acids: a computational approach. J. Comput. Biophys. Chem. https://doi.org/10.1142/S2737416524500443 (2024).
doi: 10.1142/S2737416524500443
Farrokhi, R. A. & Shahverdizadeh, G. H. Hirshfeld surface analyses, NCI–RDG and effect of surfactant on the size of Co3O4 nanostructures obtained from cobalt(II) nano-complex. J. Mol. Struct. 1294, 136400 (2023).
doi: 10.1016/j.molstruc.2023.136400
Boukabcha, N. et al. Spectral investigation, TD-DFT study, Hirshfeld surface analysis, NCI-RDG, HOMO-LUMO, chemical reactivity and NLO properties of 1-(4-fluorobenzyl)-5-bromolindolin-2,3dione. J. Mol. Struct. 1285, 135492 (2023).
Kandasamy, S. et al. In silico, theoretical biointerface analysis and in vitro kinetic analysis of amine compounds interaction with acetylcholinesterase and butyrylcholinesterase. Int. J. Biol. Macromol. 185, 750-760 (2021).