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

Abstract

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 K D 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.

A Comparison between Enrichment Optimization Algorithm (EOA)-Based and Docking-Based Virtual Screening

“…Still, our EOA results are significantly higher at 0.92 ± 0.02 and 30.2 ± 8.1 for the AUC and EF 1% , respectively. Finally, we note that while a consensus approach may benefit docking-based VS, in many projects, single structure-based VS is still the method of choice, either because of limited computational resources or because of lack of multiple crystal structures for the target of interest [ 34 , 35 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds

“…10 However, the binding mode between PCSK9 and LDLR involves a protein−protein interaction (PPI), and the interface between PCSK9 and LDLR is an extended and flat state without a deep binding pocket, which brings great challenges for designing small molecule inhibitors of PCSK9. 11 Currently, there are two monoclonal antibodies and one siRNA in clinical application. In 2015, two monoclonal antibodies, alirocumab and evolocumab, were approved by the Food and Drug Administration (FDA).…”

Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor

“…All the procedures and settings for molecular modeling were similar with those in our previous studies. − The crystal structure of ACLY in complex with NDI-091143 (PDB ID: 6O0H) was used for molecular docking. The crystal structure of ACLY contained six domains.…”