In silico discovery of CETP inhibitors from ZINC15 compounds using docking, ADMET filtering, and molecular dynamics simulations.

BACKGROUND AND PURPOSE: Cholesteryl ester transfer protein is a crucial regulator of lipid metabolism and is considered a promising target for treating atherosclerotic cardiovascular disease. Given the clinical limitations and adverse effects of previous cholesteryl ester transfer protein inhibitors, such as torcetrapib, this study aimed to identify safer, more effective alternatives through computational drug discovery. EXPERIMENTAL APPROACH: A diverse set of natural compounds from the ZINC15 database was screened using a multi-step in silico workflow comprising drug-likeness assessment, ADMET profiling, molecular docking, and molecular dynamics simulations. This integrated process narrowed down a large compound library to a refined selection of candidates with favorable safety and pharmacokinetic properties. FINDINGS/RESULTS: Calebin, a bioactive compound derived from turmeric, emerged as the most promising cholesteryl ester transfer protein inhibitor. It demonstrated binding interactions with cholesteryl ester transfer protein (-8.4 Kcal/mol) that were comparable to curcumin (-8.5 kcal/mol) and lower than the reference x-ray inhibitor torcetrapib (-9.4 kcal/mol), along with similar molecular dynamic complex stability (RMSD of 2.515 ± 0.282 Å in comparison to torcetrapib 2.502 ± 0.332 Å). CONCLUSION AND IMPLICATIONS: These findings highlight the value of computational drug discovery for identifying natural inhibitors of cholesteryl ester transfer protein and provide a strong foundation for future experimental validation. Calebin A demonstrated a promising binding affinity and interaction stability with cholesteryl ester transfer protein, but proof-of-concept studies are warranted to confirm this potential activity.