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FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
|Coordinator Country||Italy [IT]|
|Total cost||180˙277 €|
|EC max contribution||180˙277 € (100%)|
1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
|Duration (year-month-day)||from 2017-11-06 to 2019-11-05|
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|1||FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA||IT (GENOVA)||coordinator||180˙277.00|
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.
|year||authors and title||journal||last update|
Alexandria A. Oviatt, Jissy A. Kuriappan, Elirosa Minniti, Kendra R. Vann, Princess Onuorah, Anna Minarini, Marco De Vivo, Neil Osheroff
Polyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase IIÎ± and IIÎ²
published pages: 2961-2968, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.07.010
|Bioorganic & Medicinal Chemistry Letters 28/17||2020-04-08|
Jissy A. Kuriappan, Neil Osheroff, Marco De Vivo
Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II
published pages: 4007-4017, ISSN: 1549-9596, DOI: 10.1021/acs.jcim.9b00605
|Journal of Chemical Information and Modeling 59/9||2020-04-08|
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