Docking And Molecular Dynamics Study On The Inhibitors Of Cholesteryl Ester Transfer Protein (CETP)

CETP is a plasma glycoprotein that mediates the transfer of CE from highdensity lipoprotein to low density lipoprotein and very low density lipoprptein with abalanced exchange of TG. This transfer process can decrease the level ofanti-atherogenic HDL, and elevate the level of pro-atherogenic VLDL and LDL.Therefore, inhibiting CETP would be expected to provide a potential therapeuticbenefit for patients with cardiovascular diseases.In our study, we selected40compounds which obtained good biologic activitiesas ligands to dock with the CETP receptor by software Dock6.2. The active site wasall spheres within10.0Angstroms from every atom of the crystal structure of theligand. According to results of docking, we confirmed that the docking values directlycorrelated with their biologic activities. This study also identified the potentialimportant binding site of CETP.Through the docking results, we selected the N, N-disubstituted-trifluoro-3-amino-2-propanol analogues which are among the most highly potent and selectiveinhibitors of CETP for further research. For in-depth investigation into the structuraland chemical features responsible for exploring the binding pocket of thesecompounds, as well as for the binding recognition mechanism concerned, weperformed a series of automated molecular docking operations by software AutoDock1.5.2. In the end, the docking results were quite robust as further validated bymolecular dynamics.The docking results reveal that the binding site mainly consists of twohydrophobic regions (P1and P2site) which are able to accommodate the lipophilicarms of the compounds investigated. Val421in P1site and Met194in P2site could beconsidered to be two important residues in forming the two hydrophobic regions. Thepresence of residues Phe197and Phe463in P2site may be responsible for the bindingrecognition through π-π stacking interactions. The hydrophobic3-phenoxy substituentmay be important in creating the preferable inhibitive capability for increasing thebinding potency. The hydrophobic character of the tetrafluoroethoxybenzyl group atposition3displays better hydrophobicity than a shorter hydrophobic substituent.An interaction model of CETP-inhibitors is derived that can be successfully usedto explain the different biologic activities of these inhibitors. It is anticipated that thefindings reported here may provide very useful information or clues for designingeffective drugs for the therapeutic treatment of CETP-related cardiovascular diseases.