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

Sickle cell disease (SCD) is a genetic disorder marked by abnormal hemoglobin polymerization, resulting in impaired red blood cell function. Activation of pyruvate kinase (PK), a key enzyme in glycolysis, has emerged as a promising therapeutic strategy to enhance red blood cell metabolism and mitigate disease severity. This study employed a comprehensive computational approach, integrating molecular docking, density functional theory (DFT), molecular dynamics (MD) simulation, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions to identify novel allosteric activators of PK. In the virtual screening of the Enamine and Asinex libraries of chemical compounds, ten compounds were identified as top candidates with superior docking affinities and binding free energies compared to the reference compound Mitapivat. Among these, compounds Z169572442 and Z432281300 were prioritized based on their strong binding interactions with the PK protein. DFT studies on these two compounds further validated their electronic properties, including frontier molecular orbitals (FMOs), reinforcing their potential as allosteric activators. MD simulation confirmed the stability of the PK-ligand complexes, as evidenced by consistent RMSD, RMSF, and protein-ligand contact profiles. ADMET analysis revealed favorable pharmacokinetic properties, with minor water solubility and distribution concerns. These findings support the potential of Z169572442 and Z432281300 as promising PK activators and lay the groundwork for further experimental validation, aiming to develop effective therapies for SCD.