Docking and molecular dynamics study on the inhibitory activity of N, N-disubstituted-trifluoro-3-amino-2-propanols-based inhibitors of cholesteryl ester transfer protein.

Extensive studies suggest direct links between cholesteryl ester transfer protein (CETP), high-density lipoproteins-cholesterol level and cardiovascular diseases. Many therapeutic approaches are aimed at the CETP. A series of N, N-disubstituted-trifluoro-3-amino-2-propanol analogues are among the most highly potent and selective inhibitors of CETP described to date. For in-depth investigation into the structural and chemical features responsible for exploring the binding pocket of these compounds, as well as for the binding recognition mechanism concerned, we performed a series of automated molecular docking operations. Moreover, the docking results were quite robust as further validated by molecular dynamics. The docking results reveal that the binding site mainly consists of two hydrophobic regions (P1 and P2 site) which are able to accommodate the lipophilic arms of the compounds investigated. Val421 in P1 site and Met194 in P2 site could be considered to be two important residues in forming the two hydrophobic regions. The presence of residues Phe197 and Phe463 in P2 site may be responsible for the binding recognition through π-π stacking interactions. The hydrophobic 3-phenoxy substituent may be important in creating the preferable inhibitive capability for increasing the binding potency. The hydrophobic character of the tetrafluoroethoxybenzyl group at position 3 displays better hydrophobicity than a shorter hydrophobic substituent. An interaction model of CETP-inhibitors is derived that can be successfully used to explain the different biologic activities of these inhibitors. It is anticipated that the findings reported here may provide very useful information or clues for designing effective drugs for the therapeutic treatment of CETP-related cardiovascular diseases.