vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-114vavilov-4892Research ArticleСТРУКТУРНАЯ КОМПЬЮТЕРНАЯ БИОЛОГИЯSTRUCTURAL COMPUTATIONAL BIOLOGYВлияние димерных бисбензимидазолов на активность ферментов репарации ДНК тирозил-ДНК-фосфодиэстераз 1 и 2 и поли(АДФ-рибоза)полимераз 1 и 2The effect of dimeric bisbenzimidazoles on the activity of DNA repair enzymes TDP1, TDP2, PARP1 and PARP2https://orcid.org/0000-0002-8360-1041ДырхееваН. С.DyrkheevaN. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-1934-5116ЧернышоваИ. А.ChernyshovaI. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-5254-9252АрутюнянА. Ф.ArutyunyanA. F.

Москва

Moscow

https://orcid.org/0009-0004-8025-1009ЗахаренкоА. Л.ZakharenkoA. L.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-0927-4043КутузовМ. М.KutuzovM. M.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-7407-3198НауменкоК. Н.NaumenkoK. N.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-7419-5168ВензельА. С.VenzelA. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-1859-4631ИванисенкоВ. А.IvanisenkoV. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-9382-4388ДеевC. М.DeyevS. M.

Москва

Moscow

https://orcid.org/0000-0001-6230-8711ЖузеА. Л.ZhuzeA. L.

Москва

Moscow

https://orcid.org/0000-0001-5980-8889ЛаврикО. И.LavrikO. I.

Новосибирск

Novosibirsk

lavrik@1bio.ruИнститут химической биологии и фундаментальной медицины Сибирского отделения Российской академии наукРоссияInstitute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of SciencesRussian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наукРоссияThe Engelhardt Institute of Molecular Biology of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationИнститут биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наукРоссияShemyakin–Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesRussian Federation20251212202529710971108Copyright © Дырхеева Н.С., Чернышова И.А., Арутюнян А.Ф., Захаренко А.Л., Кутузов М.М., Науменко К.Н., Вензель А.С., Иванисенко В.А., Деев C.М., Жузе А.Л., Лаврик О.И., 20252025Дырхеева Н.С., Чернышова И.А., Арутюнян А.Ф., Захаренко А.Л., Кутузов М.М., Науменко К.Н., Вензель А.С., Иванисенко В.А., Деев C.М., Жузе А.Л., Лаврик О.И.Dyrkheeva N.S., Chernyshova I.A., Arutyunyan A.F., Zakharenko A.L., Kutuzov M.M., Naumenko K.N., Venzel A.S., Ivanisenko V.A., Deyev S.M., Zhuze A.L., Lavrik O.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4892

   Онкологические заболевания остаются одной из главных причин патологической смертности в мире, что определяет дизайн противораковых препаратов как ключевое направление медицинской химии. Комбинация ингибиторов ферментов репарации ДНК с ингибиторами топоизомераз – перспективный подход для усиления противоракового действия и снижения токсичности химиотерапии. Особый интерес представляют узкобороздочные ДНК-лиганды, способные эффективно ингибировать ДНК-зависимые ферменты, обладая при этом низкой токсичностью и мутагенностью. Ряд исследовательских групп, включая нашу, разрабатывает ингибиторы ферментов репарации ДНК, действующие одновременно на несколько взаимосвязанных мишеней {тирозил-ДНК-фосфодиэстеразы 1/2 (TDP1/TDP2), поли(АДФ-рибоза)полимераза 1 (PARP1)/TDP1, топоизомераза 1 (ТОР1)/TDP1}. Такие бифункциональные ингибиторы призваны решить проблему резистентности опухолевых клеток к известным химиопрепаратам и повысить эффективность последних. В настоящем исследовании представлены данные скрининга ингибирующей активности 22 узкобороздочных лигандов, взаимодействующих с ДНК, – бис- и трисбензимидазолов – в отношении четырех ферментов репарации: TDP1, TDP2, PARP1 и PARP2. Изучены четыре серии димерных соединений и их мономерных единиц. Показана разница в ингибирующей активности димерных бисбензимидазолов в зависимости от структуры соединения и фермента. Мономерные и димерные бисбензимидазолы эффективно ингибируют активность TDP1 в микромолярном и субмикромолярном диапазоне IC50 (концентрация полумаксимального ингибирования). Димерные соединения групп DB2Pу(n) и DB3P(n) проявили более значительную ингибирующую активность в отношении ферментативной реакции с участием TDP1 по сравнению с мономерами, входящими в их состав. Для всех исследованных соединений была показана низкая ингибирующая способность в отношении остальных трех ферментов репарации ДНК, т. е. наблюдается их специфическое воздействие именно на TDP1. Следует отметить, что в данной работе в экспериментах с TDP1 и TDP2 было исключено действие исследуемых соединений как узкобороздочных лигандов, связывающихся с ДНК, и исследовано их непосредственное воздействие на фермент. По результатам молекулярного докинга можно предположить возможность прямого взаимодействия изучаемых соединений с активным центром TDP1. Согласно результатам моделирования, ингибиторы располагаются в области связывания 3’-конца ДНК с активным центром TDP1 и могут образовывать устойчивые связи с каталитически значимыми остатками активного центра His263 и His493. Эти взаимодействия, вероятно, обеспечивают высокую ингибирующую активность соединений, наблюдаемую в биохимических экспериментах.

   Oncological diseases remain a leading cause of pathological mortality worldwide, making the development of anticancer drugs a critical focus in medicinal chemistry. A promising strategy to enhance therapeutic efficacy and reduce chemotherapy-induced toxicity involves the combined inhibition of DNA repair enzymes and topoisomerases. Of particular interest are minor-groove DNA ligands, which exhibit potent inhibition of DNA-dependent enzymes while having low toxicity and mutagenicity. A number of research groups, including ours, are developing inhibitors of DNA repair enzymes that act simultaneously on several targets: tyrosyl-DNA phosphodiesterase 1/2 (TDP1/TDP2), poly(ADP-ribose) polymerase 1 (PARP1)/TDP1, topoisomerase 1 (TOP1)/TDP1. Such bifunctional inhibitors are designed to resolve the problem of tumor cell resistance to known chemotherapy drugs and increase the effectiveness of the latter. In this study, we evaluated the inhibitory activity of 22 minor-groove DNA ligands – bis- and trisbenzimidazoles against four key repair enzymes: TDP1, TDP2, PARP1, and PARP2. Four series of dimeric compounds and their monomeric units were studied. The difference in inhibitory activity of dimeric bisbenzimidazoles depending on the structure of the compound and the enzyme is shown. Our findings reveal distinct structure-activity relationships, with monomeric and dimeric ligands exhibiting potent TDP1 inhibition at micromolar to submicromolar IC50 values (half-maximal inhibitory concentration). Notably, dimeric compounds from the DB2Py(n) and DB3P(n) series demonstrated superior TDP1 inhibition compared to their monomers. In contrast, all tested compounds showed negligible activity against the other three repair enzymes; so, the compounds demonstrate specificity to TDP1. It should be noted that in this work, in the experiments with TDP1 and TDP2, the effect of the tested compounds as narrow-groove ligands binding to DNA was excluded, and their direct effect on the enzyme was investigated. The results of molecular docking suggest the possibility of direct interaction of active compounds with the active center of TDP1. According to the results of modeling, the inhibitors are located in the binding region of the 3’-end of DNA in the active site of TDP1 and could form stable bonds with the catalytically significant TDP1 residues His263 and His493. These interactions probably provide the high inhibitory activity of the compounds observed in biochemical experiments.

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The authors declare that there are no conflicts of interest present.