Integration of molecular docking, molecular dynamics simulations, and free energy calculations identifies a novel flavonoid glycoside as a PCSK9 inhibitor for hypercholesterolemia

Proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly influences plasma low-density lipoprotein cholesterol (LDL-C) homeostasis by promoting the degradation of LDL receptors. While monoclonal antibody therapies are effective, their widespread application is limited by high costs and invasive administration, necessitating the development of oral small-molecule inhibitors for hypercholesterolemia management. This study evaluates the therapeutic potential of a specific flavonoid glycoside, 7-(alpha-D-Glucopyranosyloxy)-5-hydroxy-2-(4-hydroxyphenyl)-4 H-1-benzopyran-4-one, as a novel PCSK9 inhibitor using a multi-scale computational framework. The investigation integrated Density Functional Theory (DFT) calculations, ADMET profiling, molecular docking, 500 ns molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. DFT analysis revealed a HOMO-LUMO energy gap of 11.26 eV, indicating baseline chemical stability, while ADMET screening predicted a favorable safety profile with a high plasma unbound fraction (0.94). Crucially, while initial static docking primarily identified interactions with LYS222, extensive 500 ns MD simulations highlighted the inherent limitations of rigid-receptor docking. The dynamic trajectory unveiled a conformational adaptation where the ligand adjusted its orientation to establish more persistent hydrogen bonds with ASP374 and SER281, maintaining a highly stable complex at the interaction interface. Thermodynamic analysis supported this dynamically optimized binding mode (ΔG = -22.59 kcal/mol), driven synergistically by van der Waals interactions with hydrophobic residues (HIE226, PHE150) and specific electrostatic steering. Our findings elucidate the atomic-level binding mechanism of this flavonoid glycoside and demonstrate its structural and energetic suitability as a PCSK9 inhibitor. This study provides a theoretical basis for the development of natural product-based non-peptide therapeutics for the prevention and treatment of cardiovascular diseases.