Intercalation processes of copper complexes in DNA
Rodrigo Galindo-Murillo1, Juan Carlos García-Ramos2, Lena Ruiz-Azuara2
1Department of Medicinal Chemistry, College of Pharmacy, Skaggs Hall 201, University of Utah, Salt Lake City, UT 84112, USA.
Abstract:
The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these include the generation of reactive oxygen species, phosphate hydrolysis and/or base-pair intercalation. To advance in the understanding on how these ligands interact with DNA, we present a molecular dynamics study of 21 Casiopeínas with a DNA dodecamer using 10 μs of simulation time for each compound. All the complexes were manually inserted into the minor groove as the starting point of the simulations. The binding energy of each complex and the observed representative type of interaction between the ligand and the DNA is reported. With this extended sampling time, we found that four of the compounds spontaneously flipped open a base pair and moved inside the resulting cavity and four compounds formed stacking interactions with the terminal base pairs. The complexes that formed the intercalation pocket led to more stable interactions.
Insights
Copper-based anticancer drugs, Casiopeínas®, show potential in clinical trials. Molecular dynamics simulations reveal how these compounds interact with DNA, with some forming stable intercalation pockets, advancing understanding of their anticancer mechanisms.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Molecular Biology
Background:
- Casiopeínas® are copper-containing anticancer agents with promising clinical trial results.
- Their DNA interaction mechanisms, including reactive oxygen species generation and intercalation, are under investigation.
Purpose of the Study:
- To elucidate the DNA interaction mechanisms of 21 Casiopeínas® compounds.
- To understand how these ligands bind to DNA using molecular dynamics simulations.
Main Methods:
- Conducted 10 μs molecular dynamics simulations for each of 21 Casiopeínas® complexes with a DNA dodecamer.
- Initiated simulations with complexes manually inserted into the DNA minor groove.
- Analyzed binding energies and interaction types.
Main Results:
- Four Casiopeínas® compounds spontaneously intercalated into the DNA by flipping a base pair.
- Four compounds formed stacking interactions with terminal DNA base pairs.
- Intercalating complexes exhibited more stable DNA interactions.
Conclusions:
- Molecular dynamics simulations provide detailed insights into Casiopeínas®-DNA interactions.
- Specific binding modes, such as intercalation, correlate with enhanced complex stability.
- Findings contribute to the rational design of novel copper-based anticancer drugs.
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