Fragment-based discovery of novel pentacyclic triterpenoid derivatives as cholesteryl ester transfer protein inhibitors

Cholesteryl Ester Transfer Protein (CETP) is an important therapeutic target for the treatment of atherosclerotic cardiovascular disease. Our molecular modeling study revealed that pentacyclic triterpenoid compounds could mimic the protein-ligand interactions of the endogenous ligand cholesteryl ester (CE) by occupying its binding site. Alignment of the docking conformations of oleanolic acid (OA), ursolic acid (UA) and the crystal conformations of known CETP inhibitor Torcetrapib in the active site proposed the applicability of fragment-based drug design (FBDD) approaches in this study. Accordingly, a series of pentacyclic triterpenoid derivatives have been designed and synthesized as novel CETP inhibitors. The most potent compound 12e (IC50:0.28 μM) validated our strategy for molecular design. Molecular dynamics simulations illustrated that the more stable hydrogen bond interaction of the UA derivative 12e with Ser191 and stronger hydrophobic interactions with Val198, Phe463 than those of OA derivative 12b mainly led to their significantly different CETP inhibitory activity. These novel potent CETP inhibitors based on ursane-type scaffold should deserve further investigation. [Display omitted] •Linking of PTs and the active fragment provided a promising lead compound 12e.•Compound 12e took a unique CE-mimicking binding mode, different with current known CETP inhibitors.•Compound 12e with potent CETP inhibitory activity experimentally validated our molecular modeling.•Molecular dynamics simulations explained the detailed differences on CETP inhibitory activity between compound 12b and 12e.