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

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

Molecules. 2022 Apr 9;27(8):2433. doi: 10.3390/molecules27082433.

Authors

Affiliations

¹ Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia.
² Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia.
³ World-Class Research Center "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia.
⁴ Department of Computational Biology, Sirius University of Science and Technology, Olympic Ave. 1, 354340 Sochi, Russia.
⁵ Department of Physical and Chemical Biology and Biotechnology, Altai State University, Pr. Lenina 61, 656049 Barnaul, Russia.
⁶ Faculty of Chemistry, National Research University Higher School of Economics, Pokrovsky Boulevard 11-10, 101000 Moscow, Russia.
⁷ 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.

Abstract

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.

Keywords: DNA repair; Tdp1 inhibition; chirality; nucleosides; pentafuranose; stereoisomers; tyrosyl-DNA phosphodiesterase 1.

MeSH terms

Humans
Ligands
Nucleosides* / pharmacology
Phosphoric Diester Hydrolases* / chemistry

Substances

Ligands
Nucleosides
Phosphoric Diester Hydrolases
TDP1 protein, human
tyrosyl-DNA phosphodiesterase

Abstract

MeSH terms

Substances

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