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

 Dong-Kook Min  ;  Hyun-Sook Lee  ;  Narae Lee  ;  Chan Joo Lee  ;  Hyun Joo Song  ;  Ga Eul Yang  ;  Dojun Yoon  ;  Sahng Wook Park 
 YONSEI MEDICAL JOURNAL, Vol.56(5) : 1251-1257, 2015 
Journal Title
Issue Date
Animals ; Cholesterol/blood* ; Cholesterol, LDL/blood ; Hep G2 Cells ; Humans ; Mice ; Mice, Knockout ; Proprotein Convertase 9 ; Proprotein Convertases/metabolism* ; Receptors, LDL/metabolism* ; Serine Endopeptidases/metabolism* ; Small Molecule Libraries*
LDL receptor ; PCSK9 ; hypercholesterolemia ; in silico ; inhibitor ; protein-protein interaction
PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
7. Others (기타) > Dept. of Health Promotion (건강의학과) > 1. Journal Papers
Yonsei Authors
Min, Dong Kook(민동국)
Park, Sahng Wook(박상욱) ORCID logo https://orcid.org/0000-0002-9594-7074
Lee, Chan Joo(이찬주) ORCID logo https://orcid.org/0000-0002-8756-409X
Lee, Hyun Sook(이현숙)
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