Newly discovered chroman-2,4-diones neutralize the in vivo DNA damage induced by alkylation through the inhibition of Topoisomerase IIα: A story behind the molecular modeling approach
2015
Аутори:
Mladenović, MilanStanković, Nevena
Matić, Sanja
Stanić, Snežana
Mihailović, Mirjana
Mihailović, Vladimir
Katanić, Jelena
Boroja, Tatjana
Vuković, Nenad
Тип документа:
Чланак у часопису (Објављена верзија)
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© 2015 Elsevier Inc
Метаподаци
Приказ свих података о документуАпстракт:
Eight chroman-2,4-diones, namely 2a-h, previously investigated as anticoagulants, of which 2a and 2f as the most active, were evaluated as in vivo genotoxic agents in Wistar rat livers and kidneys using the comet assay. Compounds 2a, 2b, and 2f without genotoxic activity were applied prior to ethyl methanesulfonate (EMS) and diminished EMS-induced DNA damage according to the total score and percentage of reduction. EMS produce harmful O(6)-ethylguanine lesion which is incorporated in aberrant genotoxic GT and TG pairing after ATP-dependent DNA strand breaks have been catalyzed by rat Topoisomerase IIα (rTopIIα, EC 5.99.1.3). Therefore, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on the enzyme level using molecular docking and molecular dynamics simulations insamuch as it had been determined that compounds do not intercalate DNA but instead inhibit the ATPase activity. Calculations predicted that compounds inhibit ATP hydrolysis before the DNA-EMS cleavage is being catalyzed by rTopIIα, prevent EMS mutagenic and carcinogenic effects, and beside anticoagulant activity can even be applied in the cancer treatment to control the rate of anticancer alkylation drugs.
Кључне речи:
Chroman-2,4-diones; Comet assay; Molecular docking; Molecular dynamics; Topoisomerase IIaИзвор:
Biochemical Pharmacology, 2015, 98, 1, 243-266Финансирање / пројекти:
- Симултана биоремедијација и соилификација деградираних простора, за очување природних ресурса биолошки активних супстанци и развој и производњу биоматеријала и дијететских производа (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-43004)
- Преклиничка испитивања биоактивних супстанци (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41010)
- Сигнални молекули у дијабетесу: идентификација потенцијалних биолошких маркера укључених у модификацију и интеграцију сигналних путева у циљу предикције и интервенције у дијабетесу (RS-MESTD-Basic Research (BR or ON)-173020)
DOI: 10.1016/j.bcp.2015.08.106
ISSN: 0006-2952
PubMed: 26319574