Searching for possible sites of electrophils conjugation with biomolecules using molecular modeling methods

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Abstract

The ability to rapidly form adducts with nucleophilic groups of proteins, nucleic acids and lipids largely determines the toxic effects of electrophiles. Considering that the number of toxic electrophiles is practically unlimited, and they can form adducts with many molecular targets, a purely empirical approach to characterizing the adductome is obviously unproductive. The aim of this study is to develop a method for primary in silico assessment of the probability of conjugation of electrophiles with a particular modification site. For the model group of electrophiles, the quantum-chemical indices were calculated using the density functional theory method, and the molecular docking method was used to search for priority sites of covalent binding of the studied compounds. Based on the obtained results, a scale for assessing the hardness of electrophiles was developed and an algorithm for computer selection of possible conjugation sites of electrophiles with biological macromolecules was compiled.

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About the authors

D. A. Belinskaia

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: d_belinskaya@mail.ru
Russian Federation, prosp. Toreza 44, St. Petersburg, 194223

Е. I. Savelieva

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Email: d_belinskaya@mail.ru
Russian Federation, Kuzmolovsky, st. Kapitolovo 93, 188663

References

  1. Pivotal Role of Mass Spectrometry for the Assessment of Exposure to Reactive Chemical Contaminants: From the Exposome to the Adductome / Debrauwer L., Mervant L., Laprevote,O., Jamin E.L. Eds. / Wiley Periodicals LLC, 2024.
  2. Knapen M.F., Zusterzeel P.L., Peters W.H., Steegers E.A. // Eur. J. Obstet. Gynecol. Reprod. Biol. 1999. V. 82. P. 171–184. https://doi.org/10.1016/s0301-2115(98)00242-5
  3. Blum M.M., Schmeißer W., Dentzel M., Thiermann H., John H. // Anal. Bioanal. Chem. 2024. V. 416. P. 5791–5804. https://doi.org/10.1007/s00216-024-05501-8
  4. Reuter, H., Steinritz, D., Worek, F., John H. // Anal. Bioanal. Chem. 2025. V. 417. P. 1833–1845. https://doi.org/10.1007/s00216-025-05762-x
  5. Xie Z., Chen J.Y., Gao H., Keith R.J., Bhatnagar A., Lorkiewicz P., Srivastava S. // Environ. Sci. Technol. 2023. V. 57. P. 10563-10573. https://doi.org/10.1021/acs.est.2c09554
  6. La Barbera G., Shuler M.S., Beck S.H., Ibsen P.H., Lindberg L.J., Karstensen J.G., Dragsted L.O. // Talanta. 2025. V. 282. P. 126985. https://doi.org/10.1016/j.talanta.2024.126985
  7. Blair I.A. // Biomed. Chromatogr. 2010. V. 1. P. 29–38. https://doi.org/10.1002/bmc.1374
  8. Koivisto P., Peltonen K. // Anal. Bioanal. Chem. 2010. V. 398. P. 2563–2572. https://doi.org/10.1007/s00216-010-4217-3
  9. Pearson R.G. // J. Am. Chem. Soc. 1963. V. 85. P. 3533–3539. https://doi.org/10.1021/ja00905a001
  10. LoPachin R.M., Geohagen B.C., Nordstroem L.U. // Toxicology. 2019. V. 418. P. 62–69. https://doi.org/10.1016/j.tox.2019.02.005
  11. Tong G.C., Cornwell W.K., Means G.E. // Toxicol. Lett. 2004. V. 147. P. 127-131. https://doi.org/10.1016/j.toxlet.2003.10.021
  12. Hashimoto K., Aldridge W.N. // Biochem. Pharmacol. 1970. V. 19. P. 2591–2604. https://doi.org/10.1016/0006-2952(70)90009-2
  13. Springer D.L., Bull R.J., Goheen S.C., Sylvester D.M., Edmonds C.G. // J. Toxicol. Environ. Health. 1993. V. 40. P. 161–176. https://doi.org/10.1080/15287399309531785
  14. Basile A., Ferranti P., Moccaldi R., Spagnoli G., Sannolo N. // J Chromatogr A. 2008. V. 1215. P. 74-81. https://doi.org/10.1016/j.chroma.2008.10.093
  15. Luo Y.S., Long T.Y., Shen L.C., Huang S.L., Chiang S.Y., Wu K.Y. // Chem. Biol. Interact. 2015. V. 237. P. 38–46. https://doi.org/10.1016/j.cbi.2015.05.002
  16. Doerge D.R., Gamboa da Costa G., McDaniel L.P., Churchwell M.I., Twaddle N.C., Beland F.A. // Mutat. Res. 2005. V. 580. P. 131–141. https://doi.org/10.1016/j.mrgentox.2004.10.013
  17. Gan J.C., Oandasan A., Ansari G.A.S. // Chemosphere. 1991. V. 23. P. 939–947. https://doi.org/10.1016/0045-6535(91)90098-X
  18. Lassé M., Stampfli A.R., Orban T., Bothara R.K., Gerrard J.A., Fairbanks A.J., Pattinson N.R., Dobson R.C.J. // Biochim. Biophys. Acta Gen. Subj. 2021. V. 1865. е130013. https://doi.org/10.1016/j.bbagen.2021.130013
  19. Moghe A., Ghare S., Lamoreau B., Mohammad M., Barve S., McClain C., Joshi-Barve S. // Toxicol. Sci. 2015. V. 143. P. 242–255. https://doi.org/10.1093/toxsci/kfu233
  20. Wang H.T., Zhang S., Hu Y., Tang M.S. // Chem. Res. Toxicol. 2009. V. 22. P. 511–517. https://doi.org/10.1021/tx800369y
  21. LeBlanc A., Shiao T.C., Roy R., Sleno L. // Chem. Res. Toxicol. 2014. V. 27. P. 1632–1639. https://doi.org/10.1021/tx500284g
  22. Hoos J.S., Damsten M.C., de Vlieger J.S., Commandeur J.N., Vermeulen N.P., Niessen W.M., Lingeman H., Irth H. // J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2007. V. 859. P. 147–156. https://doi.org/10.1016/j.jchromb.2007.09.015
  23. Switzar L., Kwast L.M., Lingeman H., Giera M., Pieters R.H., Niessen W.M. // J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2013. V. 917–918. P. 53–61. https://doi.org/10.1016/j.jchromb.2012.12.033
  24. Axworthy D.B., Hoffmann K.J., Streeter A.J., Calleman C.J., Pascoe G.A., Baillie T.A. // Chem. Biol. Interact. 1988. V. 68. P. 99–116. https://doi.org/10.1016/0009-2797(88)90009-9
  25. Bischoff K. // Veterinary Toxicology (Third Edition) Basic and Clinical Principles / Ed. Gupta R.C. Academic Press, 2018. P. 357–384. https://doi.org/10.1016/B978-0-12-811410-0.00021-0
  26. Ozawa M., Kubo T., Lee S.H., Oe T. // J. Toxicol. Sci. 2019. V. 44. P. 559–563. https://doi.org/10.2131/jts.44.559
  27. Yin H., Guo Y., Zeng T., Zhao X., Xie K. // PLoS One. 2013. V. 8. e76011. https://doi.org/10.1371/journal.pone.0076011
  28. DeCaprio A.P., O’Neill E.A. // Toxicol. Appl. Pharmacol. 1985. V. 78. P. 235–247. https://doi.org/10.1016/0041-008x(85)90287-x
  29. Yan B., DeCaprio A.P., Zhu M., Bank S. // Chem. Biol. Interact. 1996. V. 102. P. 101–116. https://doi.org/10.1016/s0009-2797(96)03738-6
  30. DeCaprio A.P., Strominger N.L., Weber P. // Toxicol. Appl. Pharmacol. 1983. V. 68. P. 297–307. https://doi.org/10.1016/0041-008x(83)90014-5
  31. Ichihara G., Amarnath V., Valentine H.L., Takeshita T., Morimoto K., Sobue T., Kawai T., Valentine W.M. // Int. Arch. Occup. Environ. Health. 2019. V. 92. P. 873– 881. https://doi.org/10.1007/s00420-019-01430-7
  32. Wang Y., Yu H., Shi X., Luo Z., Lin D., Huang M. // J. Biol. Chem. 2013. V. 288. P. 15980-15987. https://doi.org/10.1074/jbc.M113.467027
  33. Ding A., Ojingwa J.C., McDonagh A.F., Burlingame A.L., Benet L.Z. // Proc. Natl. Acad. Sci. USA. 1993. V. 90. P. 3797–3801. https://doi.org/10.1073/pnas.90.9.3797
  34. Wu Y., Chen L., Chen J., Xue H., He Q., Zhong D., Diao X. // Drug Metab. Dispos. 2023. V. 51. P. 8–16. https://doi.org/10.1124/dmd.122.001019
  35. Scaloni A., Ferranti P., De Simone G., Mamone G., Sannolo N., Malorni A. // FEBS Lett. 1999. V. 452. P. 190–194. https://doi.org/10.1016/S0014-5793(99)00601-8
  36. Ferraro G., Massai L., Messori L., Merlino A. // Chem. Commun. (Camb). 2015. V. 51. P. 9436–9439. https://doi.org/10.1039/C5CC01751C
  37. Minet E., Cheung F., Errington G., Sterz K., Scherer G. // Biomarkers. 2011. V. 16. P. 89–96. https://doi.org/10.3109/1354750x.2010.533287
  38. Lin C.Y., Lee H.L., Sung F.C., Su T.C. // Environ. Pollut. 2018. V. 239. P. 493–498. https://doi.org/10.1016/j.envpol.2018.04.010
  39. Benz F.W., Nerland D.E., Li J., Corbett D. // Fundam. Appl. Toxicol. 1997. V. 36. P. 149–156. https://doi.org/10.1006/faat.1997.2295
  40. Walker V.E., Fennell T.R., Walker D.M., Bauer M.J., Upton P.B., Douglas G.R., Swenberg J.A. // Chem. Res. Toxicol. V. 2020. V. 33. P. 1609–1622. https://doi.org/10.1021/acs.chemrestox.0c00153
  41. Kaur S., Hollander D., Haas R., Burlingame A.L. // J. Biol. Chеm. 1989. V. 264. P. 16981–16984.
  42. Basile A., Ferranti P., Mamone G., Manco I., Pocsfalvi G., Malorni A., Acampora A., Sannolo N. // Rapid Commun Mass Spectrom. 2002. V. 16. P. 871– 878. https://doi.org/10.1002/rcm.655
  43. Greim H. // Toxicol Lett. 2003. V. 138. P. 1–8. https://doi.org/10.1016/s0378-4274(02)00408-3
  44. Rappaport S.M., Yeowell-O'Connell K., Bodell W., Yager J.W., Symanski E. // Cancer Res. 1996. V. 56. P. 5410–5416.
  45. Dai J., Zhang F., Zheng J. // Anal. Biochem. 2010. V. 405. P. 73–81. https://doi.org/10.1016/j.ab.2010.05.001
  46. Jаgr M., Mrаz J., Linhart I., Strаnskу V., Pospísil M. // Chem. Res. Toxicol. 2007. V. 20. P. 1442–1452. https://doi.org/10.1021/tx700057t
  47. Koskinen M., Plnа K. // Chem. Biol. Interact. 2000. V. 129. P. 209–229. https://doi.org/10.1016/s0009-2797(00)00206-4
  48. Yeowell-O'Connell K., Rothman N., Smith M.T., Hayes R.B., Li G., Waidyanatha S., Dosemeci M., Zhang L., Yin S., Titenko-Holland N., Rappaport S.M. // Carcinogenesis. 1998. V. 19. P. 1565–1571. https://doi.org/10.1093/carcin/19.9.1565
  49. Rappaport S.M., Yeowell-O'Connell K., Smith M.T., Dosemeci M., Hayes R.B., Zhang L., Li G., Yin S., Rothman N. // J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2002. V. 778. P. 367–374. https://doi.org/10.1016/s0378-4347(01)00457-1
  50. Grigoryan H., Edmands W.M.B., Lan Q., Carlsson H., Vermeulen R., Zhang L., Yin S.N., Li G.L., Smith M.T., Rothman N., Rappaport S.M. // Carcinogenesis. 2018. V. 39. P. 661–668. https://doi.org/10.1093/carcin/bgy042
  51. Yeowell-O’Connell K., McDonald T.A., Rappaport S.M. // Anal. Biochem. 1996. V. 237. P. 49–55. https://doi.org/10.1006/abio.1996.0199
  52. Zarth A.T., Murphy S.E., Hecht S.S. // Chem. Biol. Interact. 2015. V. 242. P. 390–395. https://doi.org/10.1016/j.cbi.2015.11.005
  53. Zheng L., Li Y., Wu D., Xiao H., Zheng S., Wang G., Sun Q. // MedComm-Oncology. 2023. V. 2. e56. https://doi.org/10.1002/mog2.56
  54. Carlsson H., Törnqvist M. // Basic Clin. Pharmacol. Toxicol. 2017. V. 121. Suppl. 3. P. 44–54. https://doi.org/10.1111/bcpt.12715
  55. van Vugt-Lussenburg B.M.A., Capinha L., Reinen J., Rooseboom M., Kranendonk M., Onderwater R.C.A., Jennings P. // Chem. Res. Toxicol. 2022. V. 35. P. 1184– 1201. https://doi.org/10.1021/acs.chemrestox.2c00067
  56. Chao M.-R., Chang Y.-J., Cooke M.S., Hu C.-W. // Trends Analyt. Chem. 2024. V. 180. е117900. https://doi.org/10.1016/j.trac.2024.117900
  57. Walmsley S.J., Guo J., Tarifa A., DeCaprio A.P., Cooke M.S., Turesky R.J., Villalta P.W. // Chem. Res. Toxicol. 2024. V. 37. P. 302–310. https://doi.org/10.1021/acs.chemrestox.3c00302
  58. Chen H.J.C. // Chem. Res. Toxicol. 2023. V. 36. P. 132– 140. https://doi.org/10.1021/acs.chemrestox.2c00354
  59. Behl T., Rachamalla M., Najda A., Sehgal A., Singh S., Sharma N., Bhatia S., Al-Harrasi A., Chigurupati S., Vargas-De-La-Cruz C., Hobani Y.H., Mohan S., Goyal A., Katyal T., Solarska E., Bungau S. // Int. J. Mol. Sci. 2021. V. 22. е10141. https://doi.org/10.3390/ijms221810141
  60. Hanwell M.D., Curtis D.E., Lonie D.C., Vandermeersch T., Zurek E., Hutchison G.R. // J. Cheminform. 2012. V. 4. P. 17. https://doi.org/10.1186/1758-2946-4-17
  61. Hein K.L., Kragh-Hansen U., Morth J.P., Jeppesen M.D., Otzen D., Møller J.V., Nissen P. // J. Struct. Biol. V. 2010. V. 171. P. 353–360. https://doi.org/10.1016/j.jsb.2010.03.014
  62. Bucci E., Razynska A., Kwansa H., Gryczynski Z., Collins J.H., Fronticelli C., Unger R., Braxenthaler M., Moult J., Ji X., Gilliland G. // Biochemistry. 1996. V. 35. P. 3418–3425. https://doi.org/10.1021/bi952446b
  63. Sinning I., Kleywegt G.J., Cowan S.W., Reinemer P., Dirr H.W., Huber R., Gilliland G.L., Armstrong R.N., Ji X., Board P.G, Olin B., Mannervik B., Jones T.A. // J. Mol. Biol. 1993. V. 232. P. 192-212. https://doi.org/10.1006/jmbi.1993.1376.
  64. Humphrey W., Dalke A., Schulten K. // J. Mol. Graph. 1996. V. 14. P. 33–38. https://doi.org/10.1016/0263-7855(96)00018-5
  65. Neese F. // Wiley Interdiscip. Rev. Comput. Mol. Sci. 2022. V. 12. e1606. https://doi.org/10.1002/wcms.1606
  66. Melnikov F., Geohagen B.C., Gavin T., LoPachin R.M., Anastas P.T., Coish P., Herr D.W. // Neurotoxicology. 2020. V. 79. P. 95–103. https://doi.org/10.1016/j.neuro.2020.04.009
  67. Eberhardt J., Santos-Martins D., Tillack A.F., Forli S. // J. Chem. Inf. Model. 2021. V. 61. P. 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203
  68. Belinskaia D.A., Savelieva E.I., Karakashev G.V., Orlova O.I., Leninskii M.A., Khlebnikova N.S., Shestakova N.N., Kiskina A.R. // Int. J. Mol. Sci. 2021. V. 22. e9021. https://doi.org/10.3390/ijms22169021

Supplementary files

Supplementary Files
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2. Fig. 1. Structures of the studied electrophiles and their reactive metabolites.

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3. Fig. 2. Productive conformation of acrylamide at potential attachment sites in hemoglobin (Hb, a) and glutathione transferase (GST, b) according to molecular docking data. Carbon atoms of acrylamide are highlighted in green. α- and β-chains of Hb are shown by white and orange ribbons, respectively. The polypeptide chain of GST is shown by yellow ribbon. GSH is a glutathione molecule in the active site of GST. Hydrogen atoms are not shown for clarity of the figure.

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4. Fig. 3. Mechanism of interaction of styrene oxide with thiol groups of cysteines.

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5. Fig. 4. Productive conformation of S-styrene oxide near α-His45 (a) and R-styrene oxide near α-Val1 of hemoglobin (b). α- and β-chains of Hb are shown by white and orange bands, respectively. Hydrogen atoms are not shown for clarity of the figure.

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