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

doi:10.3390/molecules27082433

Molecules (Apr 2022)

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

DOI: https://doi.org/10.3390/molecules27082433
Journal volume & issue: Vol. 27, no. 8
p. 2433

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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