ИСТИНА

Inhibitors of DNA repair enzymes such as tyrosyl-DNA phosphodiesterase 1 (TDP1) may be applied in antitumor treatment for overcoming the resistance to traditional DNA-damaging chemotherapy [1]. TDP1 cleaves stalled complexes, caused by irinotecan and similar drugs, where a tyrosine side chain of topoisomerase is covalently attached to a DNA strand. The TDP1 catalytic cycle offers two potential therapeutic strategies: (1) the inhibition of the first step to prevent phosphoryl transfer and (2) the inhibition of the second step to prevent the hydrolysis of the phosphohistidine intermediate [2]. We have constructed molecular models to be used in virtual screening for potential TDP1 inhibitors: the apo form, the enzyme-substrate complex, and the intermediate with catalytic His263 covalently bound to the substrate’s oligonucleotide. Analysis of the enzyme-substrate complex allowed us to identify the interactions crucial for competitive inhibition, and to reveal sulfonate-based compounds that can effectively interact with the apo form by hydrogen bonding with Lys265, Lys495, and other amino acid residues in the oligonucleotide’s phosphate group binding sites. The Lead Finder program [3] and an in-house post-docking structural filtration algorithm were used to select compounds meeting the specified structural criteria. Also, we modeled the poses of recently discovered TDP1 inhibitors – usnic acid derivatives – and demonstrated their ability to bind to the TDP1 intermediate. They occupy a cavity adjacent to the active site and may affect its conformation, thus disrupting the reactive orientation of the intermediate phosphohistidine moiety and the nucleophilic water molecule. The work was supported by RFBR (grant № 18-315-00389).