Dissecting the Structural Dynamics of Authentic Cholesteryl Ester Transfer Protein for the Discovery of Potential Lead Compounds: A Theoretical Study.

Current structural and functional investigations of cholesteryl ester transfer protein (CETP) inhibitor design are nearly entirely based on a fully active mutation (CETP Mutant ) 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 (CETP Authentic ) and CETP Mutant . Considering the structural differences between the N- and C-terminal domains of CETP Authentic and CETP Mutant , 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 CETP Authentic displays greater flexibility and pronounced curvature compared to CETP Mutant . 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, CETP Authentic facilitates the formation of a continuous tunnel in the "neck" region, while CETP Mutant 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.