Search for Possible Conjugation Sites of Electrophiles with Biomolecules by Molecular Modeling

Objective: The ability for rapid adduct formation with nucleophilic groups of proteins, nucleic acids, and lipids is among the main factors responsible for 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 was to develop a method for primary in silico assessment of the probability of conjugation of electrophiles with a particular modification site. Methods: For the model group of electrophiles, quantum-chemical indices were obtained by DFT calculations. The interaction of the electrophiles with potential sites of their covalent binding with plasma proteins was investigated with the help of molecular docking. Results and Discussion: The resulting data were used to compile a scale for assessing the hardness of electrophiles. The priority sites for covalent binding of the electrophiles to plasma proteins were determined. Conclusions: An algorithm for the computer selection of possible conjugation sites of electrophiles with biological macromolecules was developed.