Related Experiment Video

Updated: May 11, 2026

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

Artificial intelligence-driven rational design and optimization of a potent terpenoid-derived PCSK9 inhibitor

Heng Jiang1, ZiYan Huang1, HongHui Hu1

  • 1The First Clinical College, Guangdong Medical University, Zhanjiang, 524023, China.

Molecular Diversity
|May 9, 2026
PubMed

Insights

Researchers identified Molecule3 as a potential PCSK9 inhibitor for treating hypercholesterolemia and coronary heart disease. This novel compound shows high binding affinity, offering a promising therapeutic candidate.

Area of Science:

  • Medicinal Chemistry
  • Computational Biology
  • Pharmacology

Background:

  • Hypercholesterolemia significantly increases cardiovascular disease risk.
  • The PCSK9-LDLR interaction is crucial in hyperlipidemia and a target for coronary heart disease (CHD) therapies.
  • Limited clinically approved PCSK9 inhibitors necessitate novel drug discovery.

Purpose of the Study:

  • To identify novel PCSK9 inhibitors for hypercholesterolemia treatment.
  • To leverage computational methods, including AI, for drug candidate discovery and optimization.
  • To evaluate the binding affinity and stability of potential inhibitors against PCSK9.

Main Methods:

  • Pharmacophore modeling and virtual screening of 4495 terpenoid compounds.
  • Molecular docking, fragment substitution, and ADMET property prediction.
  • AI-driven structure optimization, LogitBoost activity evaluation, molecular dynamics, and free energy calculations.

Main Results:

  • Identified 14 potential candidates from initial screening, with 99 derivatives generated.
  • Molecule3 demonstrated high binding affinity (docking score: 123.629 kcal/mol) to PCSK9.
  • AI optimization and simulations confirmed Molecule3's stable complex formation with PCSK9, outperforming Brazilin.

Conclusions:

  • Molecule3 shows significant potential as a PCSK9 inhibitor based on integrated computational approaches.
  • This study highlights the synergy of traditional CADD and AI in accelerating drug discovery for hypercholesterolemia.
  • Molecule3 represents a high-priority lead compound for further preclinical development in cardiovascular disease treatment.
Keywords:
AI-driven drug discoveryCardiovascular diseaseComputer-aided drug designHypercholesterolemiaMolecular dynamics simulation (MD simulation)Proprotein convertase subtilisin/kexin type 9 (PCSK9)

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