H2020Индивидуална стипендия2017–2019

Targeting TopoII · Mechanistic studies of metal-dependent DNA cleavage in Type II topoisomerase toward the rational design of novel anticancer drugs

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2017-11-06 → 2019-11-05
Финансиране от ЕС: 180 277 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите на работа на ензима Топоизомераза II и начинът, по който лекарства като етопозид разсичат ДНК, се анализират чрез компютърни симулации. Разбирането на тези процеси помага за намаляване на тежките странични ефекти и създаването на по-ефективни противоракови лекарства.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Mechanistic studies of metal-dependent DNA cleavage in Type II topoisomerase toward therational design of novel anticancer drugs

Type II topoisomerase (TopoII) metalloenzymes play a crucial role in regulating DNA topology in replication, transcription, recombination, and repair processes. TopoII is thus a validated target for clinical antibiotics and anticancer drugs, such as etoposide (ETO). ETO is an anticancer drug that acts by inducing TopoII-mediated DNA cleavage. The drug has been reported to target both TopoII isoforms, TopoIIα and TopoIIβ. However, the contributions of the two enzyme isoforms to the therapeutic and leukemogenic properties of the drug are unclear. Further, despite the wide use of ETO as a therapeutic agent for the treatment of cancer, the drug is associated with severe side effects, such as secondary leukemias. Understanding the mode of action of such TopoII inhibitors will assist the fight against the observed severe side effects and drug resistance. Moreover, it will open a path for the synthesis of new TopoII targeting drugs. To this end, docking and MD simulations can be a vital tool to facilitate the discovery of potent TopoII inhibitors as the first step toward more effective anticancer drugs. The cancer burden in the European Union is huge. Cancer is the second most common cause of death in the E.U., with more than 3.9 million new cases and 1.9 million deaths each year.(Ferlay et al. Eur. J. Cancer, 2018, 103, 356.) Sharing 9% of the world population, Europe shares 25% of the global cancer burden. Unfortunately, the current anticancer drugs often induce harmful side effects (such as treatment-related acute myeloid leukemia) that diminish their efficacy. Additionally, the frequent development of drug resistance hampers the drug action against cancer and bacterial infections, further enhancing the socio-economic burden. Considering the rising menace of cancer, the overall objective was to employ computational methods to determine the mechanisms underlying human TopoII catalysis and deciphering the key interactions of known/potential TopoII inhibitors with TopoII. In turn, the knowledge gained will assist in the design of novel TopoII inhibitors.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Type II topoisomerase (TopoII) metalloenzymes are crucial in regulating DNA topology in replication, transcription, recombination, and repair processes. TopoII is thus a validated target for clinical antibiotics and anticancer drugs. Recent high-resolution X-ray structures of the TopoII/DNA complex showed multiple metal ions bound to the TopoII active site. On the basis of these novel findings, a unified two-metal-ion reaction mechanism for TopoII catalysis has been proposed. However, it is still not clear how this Mg-aided two-metal-ion mechanism permits TopoII to cleave and relegate back DNA strands. Building on our previous studies on metalloenzymes, we seek here to clarify TopoII’s two-metal-aided enzymatic mechanism and identify novel TopoII inhibitors, thus completing the proposer’s computational skill set, boosting her chances of establishing and leading soon an independent computational group. We propose two objectives: First, we will depict the reaction path connecting the enzymatic reactants and products in TopoII. We will achieve this using state-of-the-art computational methodologies such as molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations coupled to enhanced sampling techniques for free-energy estimates. We will thus elucidate the metal ion dynamics in TopoII catalysis, together with the metal-induced structural changes that affect the reactivity and efficiency of TopoII catalysis. Importantly, we will investigate TopoII catalysis in the presence of either the catalytic Mg or inhibitory Zn ions in the catalytic pocket. Secondly, we will integrate mechanistic insights on TopoII catalysis with the recent structural and biophysical data on TopoII to decipher drug resistance and identify new TopoII inhibitors. To this end, docking and MD simulations will be used to facilitate the discovery of potent TopoII inhibitors as a first step toward more effective anticancer drugs and new, urgently needed antibiotics.

Оригинален текст от CORDIS (на английски).

Участници

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA · GenovaКоординаторИталия