Nanosecond molecular dynamics simulations of Cdc25B and its complex with a 1,4-naphthoquinone inhibitor: Implications for rational inhibitor design

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.