Yonsei Med J.  2015 Sep;56(5):1251-1257. 10.3349/ymj.2015.56.5.1251.

In silico Screening of Chemical Libraries to Develop Inhibitors That Hamper the Interaction of PCSK9 with the LDL Receptor

  • 1Department of Biochemistry and Molecular Biology, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea. swpark64@yuhs.ac
  • 2Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 3Department of Biochemistry, Catholic Kwandong University College of Medicine, Gangneung, Korea.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR.
We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silico screening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo.
A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice.
Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.


PCSK9; in silico; protein-protein interaction; LDL receptor; hypercholesterolemia; inhibitor

MeSH Terms

Cholesterol, LDL/blood
Hep G2 Cells
Mice, Knockout
Proprotein Convertases/*metabolism
Receptors, LDL/*metabolism
Serine Endopeptidases/*metabolism
*Small Molecule Libraries
Cholesterol, LDL
Proprotein Convertases
Receptors, LDL
Serine Endopeptidases
Small Molecule Libraries
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