Related Experiment Video

Updated: Jun 5, 2025

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
08:14

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

Published on: August 28, 2018

8.1K

Repurposed drugs as PCSK9-LDLR disruptors for lipid lowering and cardiovascular disease therapeutics

Shelly Singhal Nee Shelly Aggarwal1, Divpreet Kaur1, Daman Saluja1

  • 1Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.

Molecular Diversity
|December 8, 2024
PubMed

Insights

Researchers identified Benazepril and Quinapril as potent inhibitors of the PCSK9-LDLR interaction. These drugs could be repurposed to lower LDL cholesterol and prevent cardiovascular diseases.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Computational Chemistry

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein binds to LDL receptors (LDLR), causing LDLR degradation.
  • This process reduces the clearance of LDL cholesterol from circulation, increasing cardiovascular disease risk.
  • Targeting the PCSK9-LDLR interaction is vital for managing blood cholesterol and preventing heart disease.

Purpose of the Study:

  • To screen for low molecular weight inhibitors that disrupt the PCSK9-LDLR interaction.
  • To identify potential therapeutic agents for cardiovascular disease prevention through drug repurposing.

Main Methods:

  • High-throughput virtual screening of the DrugBank database.
  • Molecular docking using CDOCKER and flexible docking.
  • Molecular dynamics (MD) simulations and MM-PBSA binding free energy calculations.
  • In vitro assays to validate inhibitor potency.

Main Results:

  • Identified four lead compounds disrupting the PCSK9-LDLR interaction.
  • Benazepril and Quinapril demonstrated the highest potency in in vitro assays.
  • These compounds show potential for repurposing as lipid-lowering agents.

Conclusions:

  • Benazepril and Quinapril are effective disruptors of the PCSK9-LDLR interaction.
  • Drug repurposing of these compounds offers a promising strategy for cardiovascular disease treatment.
  • Further investigation into these candidates could lead to novel lipid-lowering therapies.
Keywords:
BenazeprilCoronary artery diseaseDrug repurposingHypercholesterolemiaIn-silico drug designPCSK9-LDLR disruptorsQuinapril

More Related Videos

LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring08:45

LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring

Published on: November 17, 2018

13.3K
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes10:56

A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes

Published on: September 15, 2018

8.1K

Related Concept Videos

Lipid-Lowering Drugs: Statins and Miscellaneous Agents01:20

Lipid-Lowering Drugs: Statins and Miscellaneous Agents

Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
532
Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors01:20

Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors

Antiplatelet drugs emerge as frontline defenders against the insidious threat of thromboembolic diseases, where abnormal clots obstruct vital blood vessels. These drugs stand as bulwarks, inhibiting platelet aggregation and clot formation, thereby mitigating the risk of life-threatening conditions like myocardial infarction, coronary artery disease, and thrombotic strokes.
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
468
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.4K
Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers01:26

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
141
Prodrugs01:30

Prodrugs

Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...
2.5K
Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
554