Discovery of Novel Small Molecule Inhibitors Disrupting the PCSK9-LDLR Interaction

PCSK9 低密度脂蛋白受体 对接(动物) 可欣 化学 虚拟筛选 前蛋白转化酶 枯草杆菌素 生物化学 脂蛋白 胆固醇 药物发现 医学 护理部
作者
Hengzhi Sun,Jin‐Zheng Wang,Shengjie Liu,Xinyu Zhou,Liang Dai,Caiping Chen,Qing‐Long Xu,Xiaoan Wen,Keguang Cheng,Hongbin Sun,Haoliang Yuan
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:61 (10): 5269-5279 被引量:13
标识
DOI:10.1021/acs.jcim.1c00521
摘要

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.
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