The class
Fragment-based design yields a novel pentacyclic triterpenoid CETP inhibitor with sub-micromolar potency (Eur J Med Chem 2017)
Original title: Fragment-based discovery of novel pentacyclic triterpenoid derivatives as cholesteryl ester transfer protein inhibitors
Researchers used molecular modeling and fragment-based drug design to develop novel cholesteryl ester transfer protein (CETP) inhibitors from pentacyclic triterpenoid scaffolds. Docking studies showed that oleanolic acid and ursolic acid derivatives could occupy the CETP binding site used by the known inhibitor torcetrapib, and a series of ursane-type derivatives were synthesized accordingly. The most potent compound, 12e, achieved an IC50 of 0.28 uM, and molecular dynamics simulations attributed its superior activity over the related compound 12b to a more stable hydrogen bond with Ser191 and stronger hydrophobic interactions with Val198 and Phe463. The authors conclude these ursane-based CETP inhibitors merit further investigation.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.