Novel flavonoid glycoside identified as PCSK9 inhibitor via computational modeling 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 existing monoclonal antibody therapies are effective for hypercholesterolemia, their high costs and invasive administration limit widespread application. This creates a critical need for the development of oral small-molecule inhibitors that can offer a more accessible and cost-effective management strategy for LDL-C reduction.

Researchers employed a multi-scale computational framework to evaluate 7-(alpha-D-Glucopyranosyloxy)-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one as a novel PCSK9 inhibitor. The investigation integrated Density Functional Theory (DFT) calculations to assess chemical stability, ADMET profiling for safety, molecular docking to identify initial interactions, 500 ns molecular dynamics (MD) simulations to capture dynamic binding, and MM/GBSA binding free energy calculations to quantify interaction strength.

DFT analysis revealed a HOMO-LUMO energy gap of 11.26 eV, indicating baseline chemical stability. ADMET screening predicted a favorable safety profile with a high plasma unbound fraction of 0.94. While initial static docking primarily identified interactions with LYS222, extensive 500 ns MD simulations highlighted the 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 with a ΔG of -22.59 kcal/mol, driven synergistically by van der Waals interactions with hydrophobic residues (HIE226, PHE150) and specific electrostatic steering. These findings elucidate the atomic-level binding mechanism and demonstrate the structural and energetic suitability of this flavonoid glycoside as a PCSK9 inhibitor.

The 500 ns MD simulations were crucial in revealing dynamic ligand-receptor interactions, showing persistent hydrogen bonds with ASP374 and SER281 that were missed by static docking.