Related Experiment Video
Updated: Jan 23, 2026

Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual
Wanling Wu1,2, Shudan Yang3, Jie Liu2
1Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, via structure-based virtual screening with Pep2-8 as a control, we identified TPP-4, a high-affinity peptide inhibitor targeting PCSK9. Compared to Pep2-8, TPP-4 showed lower binding free energy (approximately -9.8 kcal/mol) and Kd values (Kd = 0.08 ± 0.01 μM), interacting with PCSK9's LDLR-binding domain through multiple interactions. CD spectroscopy also provided indirect evidence for these key interactions. Additionally, it stably bound to the LDLR binding domain of PCSK9 during 100 ns MD simulations. It showed good serum stability, negligible HepG2 cytotoxicity, and restored surface LDLR (EC50 = 1.12 ± 0.05 μM). In mice, TPP-4 upregulated hepatic LDLR and reduced plasma total cholesterol levels. In conclusion, these data demonstrate that TPP-4 could be a high-affinity and potent candidate peptide for ASCVD treatment.
Related Concept Videos
Peptide Identification Using Tandem Mass Spectrometry
This technique helps gather information regarding the protein from which the peptide was obtained and to study the peptides’ amino acid sequence. Identifying peptides from a complex mixture is an important component of the growing field of...
Molecular Models
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Peptide Bonds
Virtual Work
In static equilibrium, a body can experience an imaginary or virtual movement, such as displacement or rotation. The virtual work done by a force is equal to the dot product of force and virtual displacement in the direction of the force. When it comes to virtually rotating a...
Molecular and Ionic Solids
Molecular Solids
Molecular crystalline solids, such as ice, sucrose (table sugar), and iodine, are solids that are composed of neutral molecules as their constituent units. These molecules are held together by weak intermolecular forces such as London dispersion forces, dipole-dipole interactions, or hydrogen bonds, which...

