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

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.

Molecular Insights into Macromolecules Structure, Function, and Regulation

“…As for the study of cholesteryl ester transfer protein (CETP), which is a promising target for mitigating cardiovascular diseases (CVD), the absence of dynamic structural characteristics under physiological conditions (authentic CETP) impedes a comprehensive understanding of the lipid transfer mechanisms and hampers the development of CETP pharmacologic inhibition. To address this, the structural differences between authentic CETP and mutant CETP (a fully active mutation used for crystal structure elucidation) were studied with the MD simulations and electron microscope (EM) data [11]. The results revealed that the authentic CETP is more flexible and conducive to the formation of a continuous tunnel in the "neck" region, providing a more favorable lipid exchange environment in contrast to the mutant CETP, thereby resulting in a greater risk of CVD.…”