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Nanosecond molecular dynamics simulations of Cdc25B and its complex with a 1,4-naphthoquinone inhibitor: implications
Sungmin Ko1, Woojin Lee, Sangyoub Lee
1Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea.
Abstract:
Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapies due to the correlation of their overexpression with a wide variety of cancers. To gain insight into designing new potent inhibitors, we investigate the dynamic properties of Cdc25B and its complex with a 1,4-naphtoquinone inhibitor NSC 95397 by means of molecular dynamics simulations in aqueous solution. It is shown from the calculated dynamic properties that the malleability of the residues 530-532 residing at the start of C-terminal region around the active site should be responsible for the catalytic action of Cdc25B. However, binding of the inhibitor in the active site leads to a substantial decrease in the motional amplitude of the flexible residues, due to the hydrophobic interactions with the side chain of Met531. The simulation results also indicate that at least four hydrogen bonds are involved in the enzyme-inhibitor complex. Among them, the hydrogen bond between the side chain carboxylate group of Glu478 and one of the hydroxyl groups of the inhibitor is found to be the most significant binding force stabilizing the inhibitor in the active site. This result supports the previous experimental implication that the possession of a single hydroxyl group is sufficient for the inhibitory activity of 1,4-naphthoquinone inhibitors.
Insights
Cdc25B phosphatases are cancer targets. Molecular dynamics simulations reveal how inhibitors bind, stabilizing the enzyme by reducing flexibility and forming key hydrogen bonds, aiding anticancer drug design.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cdc25 phosphatases are implicated in various cancers due to overexpression.
- Their role in cell cycle regulation makes them attractive anticancer drug targets.
Purpose of the Study:
- Investigate the dynamic properties of Cdc25B.
- Analyze the binding mechanism of a 1,4-naphthoquinone inhibitor (NSC 95397) to Cdc25B using molecular dynamics.
Main Methods:
- Molecular dynamics simulations in aqueous solution.
- Analysis of dynamic properties and enzyme-inhibitor interactions.
Main Results:
- Identified flexible residues (530-532) near the active site crucial for Cdc25B catalysis.
- Observed that inhibitor binding reduces the motional amplitude of these flexible residues via hydrophobic interactions.
- Confirmed the involvement of at least four hydrogen bonds, with a significant one between Glu478 and the inhibitor's hydroxyl group.
Conclusions:
- The flexibility of residues 530-532 is key to Cdc25B's catalytic activity.
- Inhibitor binding stabilizes Cdc25B by restricting the motion of these residues.
- A single hydroxyl group on the 1,4-naphthoquinone inhibitor is sufficient for potent binding, supporting previous findings.
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