ИСТИНА

Motivation and Aim: Human lactate dehydrogenase A (LDH-A) and tyrosyl-DNA phosphodiesterase 1 (TDP-1) constitute attractive therapeutic targets in cancer metabolism [1, 2]. These enzymes convert substrates containing negatively charged carboxyl and phosphate groups. Virtual screening of compounds with a sulfo substituent that mimic abovementioned functional groups was performed to identify novel competitive inhibitors of LDH-A and TDP-1. Methods and Algorithms: Molecular models of LDH-A and TDP-1 were constructed on the basis of available crystal structures taking into account the ionization states of amino acid residues, and structural criteria for the selection of potential inhibitors were established. A library of commercially available low-molecular-weight sulfo derivatives was subjected to virtual screening. Docking of compounds into the protein models was performed using the Lead Finder software [3]. Inhibitory effects were tested in vitro against purified proteins. Results: The most effective inhibitors selected by virtual screening and experimental validation were able to form hydrogen bonds with Arg168 in the active site of LDH-A, and with Lys265 and Lys495 in the active site of TDP-1. The sulfo group of the inhibitors was shown to occupy the position of the carboxyl or phosphate group of the corresponding substrate. Dependence of inhibitory properties of sulfonates on their structure was analyzed and directions for further structural modification of compounds were proposed. Conclusion: Molecular models of human LDH-A and TDP-1 were used to screen a library of low-molecular-weight sulfonates what enabled us to identify potential inhibitors of both enzymes. The novel LDH-A and TDP-1 inhibitors will be further investigated as target-driven anticancer agents.