A molecular dynamics investigation on the inhibition mechanism of cholesteryl ester transfer protein by Anacetrapib

A decrease in high-density lipoprotein (HDL) level and an increase in atherogenic low-density lipoprotein (LDL) concentration in plasma are involved in the progress of atherosclerosis and incidence of cardiovascular diseases. Cholesteryl ester transfer protein (CETP) passes cholesteryl ester and triglyceride molecules through a hydrophobic tunnel between lipoproteins and via that decreases the HDL/LDL ratio in plasma. Thus, inhibition of CETP activity by specific inhibitors could diminish atherosclerosis occurrence. Anacetrapib as a specific reversible inhibitor of CETP by stabilizing CETP–HDL complex significantly increases the HDL/LDL ratio in plasma. For better understanding the mechanism of CETP inhibition by Anacetrapib, after docking Anacetrapib against a CETP structure, molecular dynamics simulation of CETP and CETP–Anacetrapib in an explicit water cage was performed. Analyses of acquired trajectories show that Anacetrapib increases fluctuation of residues 421–442 of CETP through hydrophobic interactions and thus disrupts the integrity of an α-helix (helix B) structure in the C-terminal concave surface. Creation of a hinge by defeat of the helix B in the C-terminal of CETP, where CETP interacts with LDL, results in missing of an α-helix (residues 436–440) and conversion of banana-shaped CETP to a hemisphere conformation. According to the obtained results, bending of the CETP structure and conversion of the secondary structure in the C-terminal domain in the presence of Anacetrapib may destabilize CETP–VLDL complex and through that shift the dynamics of CETP to the formation of the CETP–HDL complex.