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Targeting TopoII

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Mechanistic studies of metal dependent DNA cleavage in Type II topoisomerase tow...

Mechanistic studies of metal dependent DNA cleavage in Type II topoisomerase toward the rational design of novel anticancer drugs 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 dru... ver más

05/11/2019

IIT

180K€

Presupuesto del proyecto: 180K€

Líder del proyecto

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2019-11-05

MSCA-IF-2016: Individual Fellowships

I+D

Cerrada hace 8 años

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Información adicional privada

No hay información privada compartida para este proyecto. Habla con el coordinador.

1 Participantes

IIT

180.28K€ | Lider

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Duración del proyecto: 32 meses Fecha Inicio: 2017-02-09
Fecha Fin: 2019-11-05

Líder del proyecto

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 180K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto 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.

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