In Vitro and In Silico Studies of Human Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibition by Stereoisomeric Forms of Lipophilic Nucleosides: The Role of Carbohydrate Stereochemistry in Ligand-Enzyme Interactions
Nadezhda S. Dyrkheeva,
Irina A. Chernyshova,
Georgy A. Ivanov,
Yuri B. Porozov,
Anastasia A. Zenchenko,
Vladimir E. Oslovsky,
Alexandra L. Zakharenko,
Darina I. Nasyrova,
Galina N. Likhatskaya,
Sergey N. Mikhailov,
Olga I. Lavrik,
Mikhail S. Drenichev
Affiliations
Nadezhda S. Dyrkheeva
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia
Irina A. Chernyshova
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia
Georgy A. Ivanov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Yuri B. Porozov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Anastasia A. Zenchenko
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Vladimir E. Oslovsky
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Alexandra L. Zakharenko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia
Darina I. Nasyrova
Faculty of Chemistry, National Research University Higher School of Economics, Pokrovsky Boulevard 11-10, 101000 Moscow, Russia
Galina N. Likhatskaya
Laboratory of Bioassays and Mechanism of Action of Biologically Active Compounds, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of Russian Academy of Sciences, Prospekt 100 Let Vladivostoky 159, 690022 Vladivostok, Russia
Sergey N. Mikhailov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Olga I. Lavrik
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia
Mikhail S. Drenichev
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
Inhibition of human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) by different chiral lipophilic nucleoside derivatives was studied. New Tdp1 inhibitors were found in the series of the studied compounds with IC50 = 2.7–6.7 μM. It was shown that D-lipophilic nucleoside derivatives manifested higher inhibition activity than their L-analogs, and configuration of the carbohydrate moiety can influence the mechanism of Tdp1 inhibition.
