Mechanisms
Simulating CETP as it really is, not the crystallography mutant, finds a new lead compound that jams its tunnel shut (Int J Mol Sci 2023)
Original title: Dissecting the Structural Dynamics of Authentic Cholesteryl Ester Transfer Protein for the Discovery of Potential Lead Compounds: A Theoretical Study
Most structural and drug-design work on CETP relies on a fully active mutant engineered for crystallization, leaving the dynamic behaviour of authentic CETP under physiological conditions largely unstudied. This theoretical study ran molecular dynamics simulations of both authentic and mutant CETP, using their N- and C-terminal domains as ligand binding pockets for virtual screening of lead compounds. Authentic CETP showed greater flexibility and more pronounced curvature than the mutant. Virtual screening identified ZINC000006242926 as having higher binding affinity for the N- and C-termini, which reduced the size of the N- and C-openings, disrupted the continuous lipid-transfer tunnel, and increased CETP curvature. The authors conclude authentic CETP forms a continuous tunnel through its neck region that the mutant does not, and that ZINC000006242926 induces structural changes unfavourable to lipid transport, a purely computational lead-compound discovery with no biochemical assay confirmation.
Original abstract
Current structural and functional investigations of cholesteryl ester transfer protein (CETP) inhibitor design are nearly entirely based on a fully active mutation (CETPMutant) constructed for protein crystallization, limiting the study of the dynamic structural features of authentic CETP involved in lipid transport under physiological conditions. In this study, we conducted comprehensive molecular dynamics (MD) simulations of both authentic CETP (CETPAuthentic) and CETPMutant. Considering the structural differences between the N- and C-terminal domains of CETPAuthentic and CETPMutant, and their crucial roles in lipid transfer, we identified the two domains as binding pockets of the ligands for virtual screening to discover potential lead compounds targeting CETP. Our results revealed that CETPAuthentic displays greater flexibility and pronounced curvature compared to CETPMutant. Employing virtual screening and MD simulation strategies, we found that ZINC000006242926 has a higher binding affinity for the N- and C-termini, leading to reduced N- and C-opening sizes, disruption of the continuous tunnel, and increased curvature of CETP. In conclusion, CETPAuthentic facilitates the formation of a continuous tunnel in the "neck" region, while CETPMutant does not exhibit such characteristics. The ligand ZINC000006242926 screened for binding to the N- and C-termini induces structural changes in the CETP unfavorable to lipid transport. This study sheds new light on the relationship between the structural and functional mechanisms of CETP. Furthermore, it provides novel ideas for the precise regulation of CETP functions.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.