Integration of molecular docking, molecular dynamics simulations, and free energy calculations identifies a novel flavonoid glycoside as a PCSK9 inhibitor for hypercholesterolemia
5 affiliations
- 1Department of Cardiology, The Second Hospital of Hebei Medical University
- 2Department of Cardiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
- 3Department of Renal Medicine, The Second Hospital of Hebei Medical University
- 4Laboratory of Medicine, Datong Second People’s Hospital (Datong Tumor Hospital)
- 5Department of Emergency, The Second Hospital of Hebei Medical University
Abstract
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.
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BibTeX
@article{wang2026integration,
title = {{Integration of molecular docking, molecular dynamics simulations, and free energy calculations identifies a novel flavonoid glycoside as a PCSK9 inhibitor for hypercholesterolemia}},
author = {Yanwei Wang and Xian Cheng and Fang Lin and Xin Zhao and Lu Xu and Xiaolin Zhang and Shuxia Liang},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-60821-2},
url = {https://doi.org/10.1038/s41598-026-60821-2},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integration of molecular docking, molecular dynamics simulations, and free energy calculations identifies a novel flavonoid glycoside as a PCSK9 inhibitor for hypercholesterolemia
AU - Yanwei Wang
AU - Xian Cheng
AU - Fang Lin
AU - Xin Zhao
AU - Lu Xu
AU - Xiaolin Zhang
AU - Shuxia Liang
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-60821-2
UR - https://doi.org/10.1038/s41598-026-60821-2
AB - 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.
SN - 2045-2322
ER -