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

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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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