{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:41:16Z","timestamp":1780998076483,"version":"3.54.1"},"reference-count":145,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["491111487"],"award-info":[{"award-number":["491111487"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Acrylamide (ACR) is formed during food processing by Maillard reaction between sugars and proteins at high temperatures. It is also used in many industries, from water waste treatment to manufacture of paper, fabrics, dyes and cosmetics. Unfortunately, cumulative exposure to acrylamide, either from diet or at the workplace, may result in neurotoxicity. Such adverse effects arise from covalent adducts formed between acrylamide and cysteine residues of several neuronal proteins <jats:italic>via<\/jats:italic> a Michael addition reaction. The molecular determinants of acrylamide reactivity and its impact on protein function are not completely understood. Here we have compiled a list of acrylamide protein targets reported so far in the literature in connection with neurotoxicity and performed a systematic covalent docking study. Our results indicate that acrylamide binding to cysteine is favored in the presence of nearby positively charged amino acids, such as lysines and arginines. For proteins with more than one reactive Cys, docking scores were able to discriminate between the primary ACR modification site and secondary sites modified only at high ACR concentrations. Therefore, docking scores emerge as a potential filter to predict Cys reactivity against acrylamide. Inspection of the ACR-protein complex structures provides insights into the putative functional consequences of ACR modification, especially for non-enzyme proteins. Based on our study, covalent docking is a promising computational tool to predict other potential protein targets mediating acrylamide neurotoxicity.<\/jats:p>","DOI":"10.3389\/fphar.2023.1125871","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T07:04:17Z","timestamp":1677740657000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Molecular determinants of acrylamide neurotoxicity through covalent docking"],"prefix":"10.3389","volume":"14","author":[{"given":"Nicolas Pierre Friedrich","family":"Mueller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Carloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Alfonso-Prieto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1101\/2022.11.20.517210","article-title":"OpenFold: Retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization","author":"Ahdritz","year":"2022","journal-title":"bioRxiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/978-3-030-41769-7_14","article-title":"Hemoglobin: Structure, function and allostery","volume":"94","author":"Ahmed","year":"2020","journal-title":"Subcell. Biochem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"6148","DOI":"10.1021\/acs.jctc.2c00516","article-title":"Scalable constant pH molecular dynamics in GROMACS","volume":"18","author":"Aho","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"B4","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/sj.bjp.0702136","article-title":"Contributions of cysteine 114 of the human D3 dopamine receptor to ligand binding and sensitivity to external oxidizing agents","volume":"125","author":"Alberts","year":"2009","journal-title":"Brit. J. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"W537","DOI":"10.1093\/nar\/gks375","article-title":"H++ 3.0: Automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations","volume":"40","author":"Anandakrishnan","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4662","DOI":"10.1021\/acs.jctc.6b00631","article-title":"Evaluation of methods for the calculation of the pKa of cysteine residues in proteins","volume":"12","author":"Awoonor-Williams","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"B7","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and interactions using a three-track neural network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/s0161-813x(01)00024-9","article-title":"Metabolism, toxicokinetics and hemoglobin adduct formation in rats following subacute and subchronic acrylamide dosing","volume":"22","author":"Barber","year":"2001","journal-title":"Neurotoxicology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.taap.2004.05.008","article-title":"Proteomic analysis of acrylamide-protein adduct formation in rat brain synaptosomes","volume":"201","author":"Barber","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1093\/toxsci\/kfm210","article-title":"Proteomic analysis of rat striatal synaptosomes during acrylamide intoxication at a low dose rate","volume":"100","author":"Barber","year":"2007","journal-title":"Toxicol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.chroma.2008.10.093","article-title":"Proteomic approach for the analysis of acrylamide\u2013hemoglobin adducts: Perspectives for biological monitoring","volume":"1215","author":"Basile","year":"2008","journal-title":"J. Chromatogr. A"},{"key":"B13","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"D313","DOI":"10.1093\/nar\/gkw1132","article-title":"The SWISS-model repository \u2014 New features and functionality","volume":"45","author":"Bienert","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"6928","DOI":"10.1021\/acs.jmedchem.5b00746","article-title":"Development of N-(functionalized benzoyl)-homocycloleucyl-glycinonitriles as potent cathepsin K inhibitors","volume":"58","author":"Borisek","year":"2015","journal-title":"J. Med. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3864","DOI":"10.1021\/ct300119u","article-title":"Computational study of the pKa values of potential catalytic residues in the active site of monoamine oxidase B","volume":"8","author":"Borstnar","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"B17","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13321-021-00548-6","article-title":"ProLIF: A library to encode molecular interactions as fingerprints","volume":"13","author":"Bouysset","year":"2021","journal-title":"J. Cheminform."},{"key":"B18","doi-asserted-by":"publisher","first-page":"15579","DOI":"10.1021\/ja4075776","article-title":"Water networks contribute to enthalpy\/entropy compensation in protein\u2013ligand binding","volume":"135","author":"Breiten","year":"2013","journal-title":"J. Amer. Chem. Soc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"D437","DOI":"10.1093\/nar\/gkaa1038","article-title":"RCSB Protein Data Bank: Powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences","volume":"49","author":"Burley","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.21101\/cejph.a6177","article-title":"Risk of exposure to acrylamide","volume":"28","author":"Bu\u0161ov\u00e1","year":"2020","journal-title":"Cent. Eur. J. Public Health"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physrev.1996.76.1.1","article-title":"Synaptic vesicle biogenesis, docking, and fusion: A molecular description","volume":"76","author":"Calakos","year":"1996","journal-title":"Physiol. Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"8435","DOI":"10.1039\/c9ra09601a","article-title":"Water structure in solution and crystal molecular dynamics simulations compared to protein crystal structures","volume":"10","author":"Caldararu","year":"2020","journal-title":"RSC Adv."},{"key":"B23","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1186\/1471-2105-10-421","article-title":"BLAST+: Architecture and applications","volume":"10","author":"Camacho","year":"2009","journal-title":"BMC Bioinform."},{"key":"B24","first-page":"153","article-title":"Structure of serum albumin","volume-title":"Advances in Protein Chemistry","author":"Carter","year":"1994"},{"key":"B25","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1177\/0960327109350664","article-title":"Acrylamide-induced oxidative stress in human erythrocytes","volume":"28","author":"Catalgol","year":"2009","journal-title":"Hum. Exp. Toxicol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1074\/jbc.275.3.1608","article-title":"Transport-dependent accessibility of a cytoplasmic loop cysteine in the human dopamine transporter","volume":"275","author":"Chen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","article-title":"MolProbity: All-atom structure validation for macromolecular crystallography","volume":"66","author":"Chen","year":"2010","journal-title":"Acta Crystallogr. D."},{"key":"B28","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1002\/j.1460-2075.1986.tb04288.x","article-title":"The relation between the divergence of sequence and structure in proteins","volume":"5","author":"Chothia","year":"1986","journal-title":"EMBO J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41586-019-1135-1","article-title":"Serotonin transporter\u2013ibogaine complexes illuminate mechanisms of inhibition and transport","volume":"569","author":"Coleman","year":"2019","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1021\/bi0024714","article-title":"The structural basis for the perturbed pKa of the catalytic base in 4-oxalocrotonate tautomerase: Kinetic and structural effects of mutations of Phe-50","volume":"40","author":"Czerwinski","year":"2001","journal-title":"Biochemistry"},{"key":"B31","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1093\/nar\/gkv352","article-title":"ChEMBL web services: Streamlining access to drug discovery data and utilities","volume":"43","author":"Davies","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/nprot.2010.32","article-title":"The HADDOCK web server for data-driven biomolecular docking","volume":"5","author":"De Vries","year":"2010","journal-title":"Nat. Protoc."},{"key":"B33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1021\/tx050312l","article-title":"Cytosolic and nuclear protein targets of thiol-reactive electrophiles","volume":"19","author":"Dennehy","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1021\/ja026939x","article-title":"HADDOCK: A protein-protein docking approach based on biochemical or biophysical information","volume":"125","author":"Dominguez","year":"2003","journal-title":"J. Amer. Chem. Soc."},{"key":"B35","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1179\/1476830513Y.0000000065","article-title":"Acrylamide neurotoxicity","volume":"17","author":"Erkekoglu","year":"2014","journal-title":"Nutr. Neurosci."},{"key":"B36","volume-title":"Commission Regulation (EU) 2017\/2158 of 20 November 2017 establishing mitigation measures and benchmark levels for the reduction of the presence of acrylamide in food","year":"2017"},{"key":"B12","first-page":"e07293","article-title":"Assessment of the genotoxicity of acrylamide","volume":"20","author":"Benford","year":"2022","journal-title":"EFSA J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"7075","DOI":"10.1038\/s41598-019-43647-z","article-title":"Further characterization of the zebrafish model of acrylamide acute neurotoxicity: Gait abnormalities and oxidative stress","volume":"9","author":"Faria","year":"2019","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"7918","DOI":"10.1038\/s41598-018-26343-2","article-title":"Acrylamide acute neurotoxicity in adult zebrafish","volume":"8","author":"Faria","year":"2018","journal-title":"Sci. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1080\/15216540500404093","article-title":"The extraordinary ligand binding properties of human serum albumin","volume":"57","author":"Fasano","year":"2005","journal-title":"IUBMB Life"},{"key":"B40","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.aca.2010.10.042","article-title":"Modification of major plasma proteins by acrylamide and glycidamide: Preliminary screening by nano liquid chromatography with tandem mass spectrometry","volume":"684","author":"Feng","year":"2011","journal-title":"Anal. Chim. Acta"},{"key":"B41","doi-asserted-by":"publisher","first-page":"5817","DOI":"10.1016\/s0021-9258(18)42626-9","article-title":"Cysteine 254 of the 73-kDa A subunit is responsible for inhibition of the coated vesicle (H+)-ATPase upon modification by sulfhydryl reagents","volume":"267","author":"Feng","year":"1992","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"13224","DOI":"10.1016\/s0021-9258(17)36822-9","article-title":"Inhibition of vacuolar H+-ATPase by disulfide bond formation between cysteine 254 and cysteine 532 in subunit A","volume":"269","author":"Feng","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B43","doi-asserted-by":"crossref","first-page":"431","DOI":"10.5772\/22490","article-title":"Acrylamide binding to its cellular targets: Insights from computational studies","volume-title":"Computational biology and applied bioinformatics","author":"Ferreira de Lima","year":"2011"},{"key":"B44","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1006\/jmbi.2001.4767","article-title":"Structure, dynamics and electrostatics of the active site of glutaredoxin 3 from Escherichia coli: Comparison with functionally related proteins","volume":"310","author":"Foloppe","year":"2001","journal-title":"J. Mol. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"8720","DOI":"10.1021\/jf800965y","article-title":"Carcinogenicity of acrylamide: A computational study","volume":"56","author":"Galesa","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/0165-6147(93)90029-j","article-title":"Molecular characterization of the dopamine transporter","volume":"14","author":"Giros","year":"1993","journal-title":"Trends Pharmacol. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1107\/s1600576716018719","article-title":"How many water molecules are detected in X-ray protein crystal structures?","volume":"50","author":"Gnesia","year":"2017","journal-title":"J. Appl. Crystallogr."},{"key":"B48","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1080\/02652030701243119","article-title":"Acrylamide in coffee: Review of progress in analysis, formation and level reduction","volume":"24","author":"Guenther","year":"2007","journal-title":"Food Addit. Contam."},{"key":"B49","doi-asserted-by":"publisher","first-page":"7759","DOI":"10.1016\/j.tet.2011.08.002","article-title":"Fluorescence turn-on probe for biothiols: Intramolecular hydrogen bonding effect on the Michael reaction","volume":"67","author":"Ha","year":"2011","journal-title":"Tetrahedron"},{"key":"B50","volume-title":"HADDOCK covalent docking tutorial","year":"2018"},{"key":"B51","doi-asserted-by":"publisher","first-page":"4821","DOI":"10.1021\/acs.jcim.9b00754","article-title":"GPU-Accelerated implementation of continuous constant pH molecular dynamics in Amber: pKa predictions with single-pH simulations","volume":"59","author":"Harris","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"B52","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1146\/annurev-biophys-083012-130351","article-title":"Contemporary NMR studies of protein electrostatics","volume":"44","author":"Hass","year":"2015","journal-title":"Annu. Rev. Biophys."},{"key":"B53","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1007\/s003359900249","article-title":"Localization of human and mouse N-ethylmaleimide-sensitive factor (NSF) gene: A two-domain member of the AAA family that is involved in membrane fusion","volume":"7","author":"Hoyle","year":"1996","journal-title":"Mamm. Genome"},{"key":"B54","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"B55","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1104\/pp.110.1.97","article-title":"The kinetics of N-ethylmaleimide inhibition of a vacuolar H+-ATPase and determination of nucleotide dissociation constants","volume":"110","author":"Hunt","year":"1996","journal-title":"Plant Physiol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"3038","DOI":"10.1016\/s0021-9258(19)85848-9","article-title":"Interaction between hemoglobin subunits in the hemoglobin-haptoglobin complex","volume":"255","author":"Hwang","year":"1980","journal-title":"J. Biol. Chem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.brainresbull.2020.02.001","article-title":"Unraveling correlative roles of dopamine transporter (DAT) and Parkin in Parkinson\u2019s disease (PD) \u2013 a road to discovery?","volume":"157","author":"Jayaramayya","year":"2020","journal-title":"Brain Res. Bull."},{"key":"B58","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1074\/mcp.M000051-MCP201","article-title":"Building macromolecular assemblies by information-driven docking: Introducing the HADDOCK multibody docking server","volume":"9","author":"Karaca","year":"2010","journal-title":"Mol. Cell. Proteomics"},{"key":"B60","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1126\/science.164.3881.788","article-title":"Non-Darwinian evolution","volume":"164","author":"King","year":"1969","journal-title":"Science"},{"key":"B61","doi-asserted-by":"publisher","first-page":"D335","DOI":"10.1093\/nar\/gkaa1080","article-title":"GPCRdb in 2021: Integrating GPCR sequence, structure and function","volume":"49","author":"Kooistra","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1002\/jbt.21717","article-title":"Acrylamide influence on activity of acetylcholinesterase, thiol groups, and malondialdehyde content in the brain of Swiss mice","volume":"29","author":"Kopanska","year":"2015","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s10822-018-0148-4","article-title":"Protein-ligand pose and affinity prediction: Lessons from D3R grand challenge 3","volume":"33","author":"Koukos","year":"2019","journal-title":"J. Comput. Aided Mol. Des."},{"key":"B64","doi-asserted-by":"publisher","first-page":"9011","DOI":"10.1021\/jf9014763","article-title":"Investigations on the effect of amino acids on acrylamide, pyrazines, and Michael addition products in model systems","volume":"57","author":"Koutsidis","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"B65","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3389\/fnut.2018.00014","article-title":"Dietary acrylamide and the risks of developing cancer: Facts to ponder","volume":"5","author":"Kumar","year":"2018","journal-title":"Front. Nutr."},{"key":"B66","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s10822-017-0049-y","article-title":"Performance of HADDOCK and a simple contact-based protein\u2013ligand binding affinity predictor in the D3R Grand Challenge 2","volume":"32","author":"Kurkcuoglu","year":"2018","journal-title":"J. Comput. Aided Mol. Des."},{"key":"B67","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/jat.3144","article-title":"Acrylamide induces locomotor defects and degeneration of dopamine neurons in Caenorhabditis elegans","volume":"36","author":"Li","year":"2015","journal-title":"J. Appl. Toxicol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"617366","DOI":"10.3389\/fcell.2021.617366","article-title":"pCysMod: Prediction of multiple cysteine modifications based on deep learning framework","volume":"9","author":"Li","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1093\/nar\/gkp934","article-title":"T3DB: A comprehensively annotated database of common toxins and their targets","volume":"38","author":"Lim","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"B70","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0167-4838(94)90077-9","article-title":"Determination of the catalytic site of creatine kinase by site-directed mutagenesis","volume":"1206","author":"Lin","year":"1994","journal-title":"Biochem. Biophys. Acta"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1101\/2022.07.20.500902","article-title":"Evolutionary-scale prediction of atomic level protein structure with a language model","author":"Lin","year":"2022","journal-title":"bioRxiv"},{"key":"B72","doi-asserted-by":"publisher","first-page":"17","DOI":"10.4161\/mabs.4.1.18347","article-title":"Disulfide bond structures of IgG molecules: Structural variations, chemical modifications and possible impacts to stability and biological function","volume":"4","author":"Liu","year":"2012","journal-title":"mAbs"},{"key":"B73","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/toxsci\/kfm301","article-title":"Molecular mechanisms of the conjugated \u03b1, \u03b2-unsaturated carbonyl derivatives: Relevance to neurotoxicity and neurodegenerative diseases","volume":"104","author":"LoPachin","year":"2008","journal-title":"Toxicol. Sci."},{"key":"B74","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1093\/toxsci\/kfl127","article-title":"Structure-toxicity analysis of type-2 alkenes: In vitro neurotoxicity","volume":"95","author":"LoPachin","year":"2007","journal-title":"Toxicol. Sci."},{"key":"B75","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1093\/toxsci\/kfl066","article-title":"Synaptic cysteine sulfhydryl groups as targets of electrophilic neurotoxicants","volume":"94","author":"LoPachin","year":"2006","journal-title":"Toxicol. Sci."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1289\/ehp.1205432","article-title":"Molecular mechanism of acrylamide neurotoxicity: Lessons learned from organic chemistry","volume":"120","author":"LoPachin","year":"2012","journal-title":"Environ. Health Perspect."},{"key":"B77","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.ijbiomac.2008.11.003","article-title":"The effects of acrylamide on brain creatine kinase: Inhibition kinetics and computational docking simulation","volume":"44","author":"L\u00fc","year":"2009","journal-title":"Int. J. Biol. Macromol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"5307","DOI":"10.1021\/acs.jcim.1c01278","article-title":"Mechanism-based and computational-driven covalent drug design","volume":"61","author":"Luo","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1021\/bc015519e","article-title":"Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids","volume":"12","author":"Lutolf","year":"2001","journal-title":"Bioconj. Chem."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1021\/ct100715x","article-title":"Absolute pKa values and solvation structure of amino acids from Density Functional based molecular dynamics simulation","volume":"7","author":"Mangold","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"B81","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1089\/ars.2010.3561","article-title":"Redox biology: Computational approaches to the investigation of functional cysteine residues","volume":"15","author":"Marino","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"B82","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-94-007-5787-5_7","article-title":"Computational redox biology: Methods and applications","volume-title":"Oxidative stress and redox regulation","author":"Marino","year":"2013"},{"key":"B83","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1021\/tx200437y","article-title":"Molecular mechanism of glyceraldehyde-3-phosphate dehydrogenase inactivation by \u03b1, \u03b2-unsaturated carbonyl derivatives","volume":"24","author":"Martyniuk","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/s0092-8674(03)00803-1","article-title":"Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor","volume":"115","author":"Matsushita","year":"2003","journal-title":"Cell."},{"key":"B85","doi-asserted-by":"publisher","first-page":"21991","DOI":"10.1074\/jbc.R100013200","article-title":"Unraveling the mechanism of the vesicle transport ATPase NSF, the N-ethylmaleimide-sensitive factor","volume":"276","author":"May","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B86","doi-asserted-by":"publisher","first-page":"10288","DOI":"10.1021\/acs.jpcb.6b08109","article-title":"Preferred hydrogen-bonding partners of cysteine: Implications for regulating Cys functions","volume":"120","author":"Mazmanian","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"B87","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/bs.vh.2014.12.009","article-title":"The structure and function of the dopamine transporter and its role in CNS diseases","volume":"98","author":"McHugh","year":"2015","journal-title":"Vitam. Horm."},{"key":"B88","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1093\/nar\/gky1075","article-title":"ChEMBL: Towards direct deposition of bioassay data","volume":"47","author":"Mendez","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B89","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/s1357-2725(01)00079-6","article-title":"Effects of acrylamide on creatine kinase from rabbit muscle","volume":"33","author":"Meng","year":"2001","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1124\/pr.114.009944","article-title":"What can crystal ctructures of aminergic receptors tell us about designing subtype-selective ligands?","volume":"67","author":"Michino","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e26768","DOI":"10.1002\/qua.26768","article-title":"The role of quantum chemistry in covalent inhibitor design","volume":"122","author":"Mihalovits","year":"2022","journal-title":"Int. J. Quantum Chem."},{"key":"B92","doi-asserted-by":"publisher","first-page":"4601","DOI":"10.1021\/acs.biochem.0c00782","article-title":"Exploring the mechanism of covalent inhibition: Simulating the binding free energy of \u03b1-ketoamide inhibitors of the main protease of SARS-CoV-2","volume":"59","author":"Mondal","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"B93","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/419448a","article-title":"Acrylamide is formed in the Maillard reaction","volume":"419","author":"Mottram","year":"2002","journal-title":"Nature"},{"key":"B94","doi-asserted-by":"publisher","first-page":"106848","DOI":"10.1016\/j.ntt.2019.106848","article-title":"Neuron-specific toxicity of chronic acrylamide exposure in C. elegans","volume":"77","author":"Murray","year":"2020","journal-title":"Neurotoxicol. Teratol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1007\/s00204-019-02484-9","article-title":"Proteomic analysis of hippocampal proteins in acrylamide-exposed Wistar rats","volume":"93","author":"Nagashima","year":"2019","journal-title":"Arch. Toxicol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1021\/cm402180t","article-title":"The thiol-michael addition click reaction: A powerful and widely used tool in materials chemistry","volume":"26","author":"Nair","year":"2014","journal-title":"Chem. Mat."},{"key":"B97","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s00204-003-0484-5","article-title":"Modification of human serum albumin by acrylamide at cysteine-34: A basis for a rapid biomonitoring procedure","volume":"77","author":"Noort","year":"2003","journal-title":"Arch. Toxicol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1093\/bioinformatics\/btt249","article-title":"Relation between sequence and structure in membrane proteins","volume":"29","author":"Olivella","year":"2013","journal-title":"Bioinformatics"},{"key":"B99","doi-asserted-by":"publisher","first-page":"baz024","DOI":"10.1093\/database\/baz024","article-title":"PKAD: A database of experimentally measured pKa values of ionizable groups in proteins","volume":"2019","author":"Pahari","year":"2019","journal-title":"Database"},{"key":"B100","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1002\/qua.24610","article-title":"Trapping acrylamide by a Michael addition: A computational study of the reaction between acrylamide and niacin","volume":"114","author":"Papamokos","year":"2014","journal-title":"Int. J. Quantum Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"4399","DOI":"10.1523\/JNEUROSCI.22-11-04399.2002","article-title":"Peroxynitrite inactivates the human dopamine transporter by modification of cysteine 342: Potential mechanism of neurotoxicity in dopamine neurons","volume":"22","author":"Park","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/j.1432-1033.1980.tb06022.x","article-title":"Reactivity of the thiol group in human and bovine albumin at pH 3\u20139, as measured by exchange with 2,2\u2019-dithiodipyridine","volume":"106","author":"Pedersen","year":"1980","journal-title":"Eur. J. Biochem."},{"key":"B103","doi-asserted-by":"publisher","first-page":"3843","DOI":"10.3390\/ijerph10093843","article-title":"Neurotoxicity of acrylamide in exposed workers","volume":"10","author":"Pennisi","year":"2013","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B104","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1146\/annurev.bi.48.070179.001551","article-title":"Regulation of oxygen affinity of hemoglobin: Influence of structure of the globin on the heme iron","volume":"48","author":"Perutz","year":"1979","journal-title":"Annu. Rev. Biochem."},{"key":"B105","first-page":"1","article-title":"SwissBioPics \u2014 An interactive library of cell images for the visualization of subcellular location data","author":"Philippe","year":"2022","journal-title":"Database"},{"key":"B106","doi-asserted-by":"publisher","first-page":"324","DOI":"10.2174\/13892029113149990009","article-title":"Genome-wide membrane protein structure prediction","volume":"14","author":"Piccoli","year":"2013","journal-title":"Curr. Genomics"},{"key":"B107","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1038\/s41467-021-22385-9","article-title":"Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters","volume":"12","author":"Pidathala","year":"2021","journal-title":"Nat. Commun."},{"key":"B108","doi-asserted-by":"publisher","first-page":"41","DOI":"10.2741\/s130","article-title":"Acrylamide in health and disease","volume":"3","author":"Pruser","year":"2011","journal-title":"Front. Biosci. (Sch. Ed.)"},{"key":"B109","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41598-019-57142-y","article-title":"Targeting redox metabolism: The perfect storm induced by acrylamide poisoning in the brain","volume":"10","author":"Rald\u00faa","year":"2020","journal-title":"Sci. Rep."},{"key":"B110","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1093\/jnci\/94.12.876","article-title":"Acrylamide and cancer: Tunnel leak in Sweden prompted studies","volume":"94","author":"Reynolds","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"B111","doi-asserted-by":"publisher","first-page":"17715","DOI":"10.1021\/jp0517192","article-title":"pKa Calculations in solution and proteins with QM\/MM free energy perturbation simulations: A quantitative yest of QM\/MM protocols","volume":"109","author":"Riccardi","year":"2005","journal-title":"J. Phys. Chem. B"},{"key":"B112","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1089\/ars.2012.4521","article-title":"Understanding the pka of redox cysteines: The key role of hydrogen bonding","volume":"18","author":"Roos","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"B113","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1472-6807-11-6","article-title":"Graphical analysis of pH-dependent properties of proteins predicted using PROPKA","volume":"11","author":"Rostkowski","year":"2011","journal-title":"BMC Struct. Biol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"13635","DOI":"10.1074\/jbc.M006588200","article-title":"Anesthetic-like interactions of nitric oxide with albumin and hemeproteins. A mechanism for control of protein function","volume":"276","author":"Sampath","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B115","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1021\/acs.jcim.8b00228","article-title":"Comparative evaluation of covalent docking tools","volume":"58","author":"Scarpino","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"B116","doi-asserted-by":"publisher","first-page":"3807","DOI":"10.1080\/10408398.2019.1708264","article-title":"Acrylamide in coffee: Formation and possible mitigation strategies \u2013 a review","volume":"60","author":"Schouten","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B117","doi-asserted-by":"publisher","first-page":"205","DOI":"10.33549\/physiolres.933381","article-title":"Acrylamide: A common food toxin related to physiological functions and health","volume":"66","author":"Semla","year":"2017","journal-title":"Physiol. Res."},{"key":"B118","doi-asserted-by":"publisher","first-page":"4210","DOI":"10.3390\/ijms10104210","article-title":"Effects of acrylamide on the activity and structure of human brain creatine kinase","volume":"10","author":"Sheng","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"B119","doi-asserted-by":"crossref","first-page":"8281","DOI":"10.1016\/S0021-9258(18)83180-5","article-title":"Characterization of a H+-ATPase in rat brain synaptic vesicle","volume":"264","author":"Shulamit","year":"1989","journal-title":"J. Biol. Chem."},{"key":"B120","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1002\/jcc.21222","article-title":"MCCE2: Improving protein pKa calculations with extensive side chain rotamer sampling","volume":"30","author":"Song","year":"2009","journal-title":"J. Comput. Chem."},{"key":"B121","doi-asserted-by":"publisher","first-page":"1800062","DOI":"10.1002\/minf.201800062","article-title":"Docking of covalent ligands: Challenges and approaches","volume":"37","author":"Sotriffer","year":"2018","journal-title":"Mol. Inf."},{"key":"B122","doi-asserted-by":"publisher","first-page":"2586","DOI":"10.1021\/bi00432a036","article-title":"Role of the histidine 176 residue in glyceraldehyde-3-phosphate dehydrogenase as probed by site-directed mutagenesis","volume":"28","author":"Soukri","year":"1989","journal-title":"Biochemistry"},{"key":"B123","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1093\/bioinformatics\/btx181","article-title":"Cpipe: A comprehensive computational platform for sequence and structure-based analyses of cysteine residues","volume":"33","author":"Soylu","year":"2017","journal-title":"Bioinformatics"},{"key":"B124","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/prot.24978","article-title":"Cy-preds: An algorithm and a web service for the analysis and prediction of cysteine reactivity","volume":"84","author":"Soylu","year":"2015","journal-title":"Bioinformatics"},{"key":"B125","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1186\/s12859-019-3019-7","article-title":"HH-suite3 for fast remote homology detection and deep protein annotation","volume":"20","author":"Steinegger","year":"2019","journal-title":"BMC Bioinform."},{"key":"B126","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1021\/bi9510789","article-title":"4-Oxalocrotonate tautomerase: pH dependence of catalysis and pKa values of active site residues","volume":"35","author":"Stivers","year":"1996","journal-title":"Biochemistry"},{"key":"B127","doi-asserted-by":"publisher","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Sunghwan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B128","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1136\/oem.2006.030130","article-title":"Mortality study update of acrylamide workers","volume":"64","author":"Swaen","year":"2007","journal-title":"J. Occup. Environ. Med."},{"key":"B129","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/0378-4274(85)90188-2","article-title":"Effect of acrylamide and related compounds on glycolytic enzymes of rat brain","volume":"26","author":"Tanii","year":"1985","journal-title":"Toxicol. Lett."},{"key":"B130","doi-asserted-by":"publisher","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: A worldwide hub of protein knowledge","volume":"47","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B131","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.toxlet.2003.10.021","article-title":"Reactions of acrylamide with glutathione and serum albumin","volume":"147","author":"Tong","year":"2004","journal-title":"Toxicol. Lett."},{"key":"B132","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.jmb.2015.09.014","article-title":"The HADDOCK2.2 web server: User-friendly integrative modeling of biomolecular complexes","volume":"428","author":"van Zundert","year":"2016","journal-title":"J. Mol. Biol."},{"key":"B133","doi-asserted-by":"publisher","first-page":"11464","DOI":"10.1021\/bi0607002","article-title":"Exploring the role of the active site cysteine in human muscle creatine kinase","volume":"45","author":"Wang","year":"2006","journal-title":"Biochemistry"},{"key":"B134","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1021\/acs.jpclett.9b02913","article-title":"First-principles calculation of water pKa using the newly developed SCAN functional","volume":"11","author":"Wang","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"B135","volume-title":"Computer modeling of chemical reactions in enzymes and solutions","author":"Warshel","year":"1991"},{"key":"B136","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0022-2836(76)90311-9","article-title":"Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme","volume":"103","author":"Warshel","year":"1976","journal-title":"J. Mol. Biol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B138","first-page":"28512","article-title":"The mechanism of the amidases. mutating the glutamate adjacent to the catalytic triad inactivates the enzyme due to substrate mispositioning","volume":"288","author":"Weber","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B139","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1046\/j.1471-4159.2001.00125.x","article-title":"Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter","volume":"76","author":"Whitehead","year":"2001","journal-title":"J. Neurochem."},{"key":"B140","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1002\/pro.3330","article-title":"MolProbity: More and better reference data for improved all-atom structure validation","volume":"27","author":"Williams","year":"2018","journal-title":"Protein Sci."},{"key":"B141","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1093\/nar\/gku1004","article-title":"T3db: The toxic exposome database","volume":"43","author":"Wishart","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B142","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.1016\/j.febslet.2007.03.032","article-title":"Cellular functions of NSF: Not just SNAPs and SNAREs","volume":"581","author":"Zhao","year":"2007","journal-title":"FEBS Lett."},{"key":"B143","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.neuro.2019.09.005","article-title":"Proteomic profiling of primary astrocytes and co-cultured astrocytes\/microglia exposed to acrylamide","volume":"75","author":"Zhao","year":"2019","journal-title":"Neurotoxicology"},{"key":"B144","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nature14148","article-title":"Mechanistic insights into the recycling machine of the SNARE complex","volume":"518","author":"Zhao","year":"2015","journal-title":"Nature"},{"key":"B145","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1021\/ci500118s","article-title":"Docking covalent inhibitors: A parameter free approach to pose prediction and scoring","volume":"54","author":"Zhu","year":"2014","journal-title":"J. Chem. Inf. Model."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1125871\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T07:04:31Z","timestamp":1677740671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1125871\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":145,"alternative-id":["10.3389\/fphar.2023.1125871"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1125871","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,2]]},"article-number":"1125871"}}