Related Experiment Video
Updated: Aug 14, 2026
14:37
Modeling an Enzyme Active Site using Molecular Visualization Freeware
Published on: December 25, 2021
From structural insight to molecule: Integrative molecular simulations identify candidate pyruvate kinase activators
Doni Dermawan1, Nasser Alotaiq2
1Department of Applied Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland.
Plos One
|August 12, 2026
Summary
Researchers identified novel drug candidates, CHEMBL3729403 and CHEMBL3729860, as potential activators for pyruvate kinase (PKLR) to treat pyruvate kinase deficiency (PKD), showing improved binding and pharmacokinetic properties over existing treatments.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Biology
Background:
- Pyruvate kinase (PKLR) is crucial for red blood cell energy.
- Mitapivat is an approved PKLR activator for pyruvate kinase deficiency (PKD), but has limitations.
- Improved PKLR activators are needed for PKD treatment.
Purpose of the Study:
- Identify novel Mitapivat-derived scaffolds with enhanced PKLR binding and drug-like properties.
- Utilize an integrated computational approach for drug discovery.
- Develop potential therapeutic agents for pyruvate kinase deficiency.
Main Methods:
- Screened 190 derivatives using molecular docking and pharmacophore modeling.
- Conducted molecular dynamics (MD) simulations and MM/PBSA free energy calculations.
- Assessed ADMET properties and synthetic feasibility for lead compounds.
Main Results:
- CHEMBL3729403 and CHEMBL3729860 showed superior predicted binding affinity and stability compared to Mitapivat.
- MM/PBSA calculations indicated stronger binding free energies for the novel candidates.
- ADMET profiling predicted favorable pharmacokinetic properties and safety profiles for CHEMBL3729403 and CHEMBL3729860.
Conclusions:
- CHEMBL3729403 and CHEMBL3729860 are promising PKLR activators with enhanced predicted properties.
- These compounds offer potential therapeutic advantages over Mitapivat for PKD.
- Further experimental validation is warranted to confirm their efficacy in treating PKD.
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