Exploring potential allosteric activators of pyruvate Kinase: Insights from molecular docking, DFT and dynamics...

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Sickle cell disease (SCD) is a genetic blood disorder caused by abnormal hemoglobin.
• Pyruvate kinase (PK) activation is a potential therapeutic strategy to improve red blood cell function in SCD.

Purpose of the Study:

• To identify novel allosteric activators of pyruvate kinase (PK) for sickle cell disease (SCD) treatment.
• To computationally screen chemical libraries for potential PK activators.

Main Methods:

• Molecular docking, density functional theory (DFT), and molecular dynamics (MD) simulations were used.
• Virtual screening of Enamine and Asinex chemical libraries was performed.
• Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were conducted.

Main Results:

• Ten compounds showed superior docking affinities and binding free energies compared to Mitapivat.
• Compounds Z169572442 and Z432281300 demonstrated strong binding interactions with PK.
• DFT and MD simulations confirmed the stability and electronic properties of the PK-ligand complexes.
• ADMET analysis indicated favorable pharmacokinetic profiles for the lead compounds.

Conclusions:

• Z169572442 and Z432281300 are promising candidates for PK activators.
• These compounds could form the basis for developing novel sickle cell disease therapies.
• Further experimental validation is warranted to confirm their therapeutic potential.