From structural insight to molecule: Integrative molecular simulations identify candidate pyruvate kinase activators
Abstract
Pyruvate kinase (PKLR) is a key glycolytic enzyme that regulates red blood cell energy homeostasis. Although Mitapivat is the first approved allosteric activator for pyruvate kinase deficiency (PKD), its clinical utility is limited by metabolic and pharmacokinetic challenges, underscoring the need for improved analogues. This study aimed to identify novel Mitapivat-derived scaffolds with enhanced PKLR binding, stability, and drug-like properties using an integrated computational approach. A total of 190 structurally related derivatives were screened through molecular docking, pharmacophore modeling, frontier molecular orbital (HOMO-LUMO) analysis, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, ADMET profiling, and retrosynthetic feasibility assessment. Comparative analyses were performed against Mitapivat and phenylalanine, an endogenous PKLR inhibitor. Among the screened compounds, CHEMBL3729403 and CHEMBL3729860 emerged as the most promising candidates. CHEMBL3729403 exhibited the strongest docking affinity (-9.10 kcal/mol) and superior MD stability, with the lowest average RMSD (0.419 nm) and highest hydrogen-bond occupancy (1.039). MM/PBSA calculations revealed stronger binding free energies for CHEMBL3729403 (-26.39 ± 3.21 kcal/mol) and CHEMBL3729860 (-23.05 ± 3.59 kcal/mol) than Mitapivat (-21.35 ± 3.46 kcal/mol) and phenylalanine (-3.89 ± 3.91 kcal/mol). Pharmacophore analysis demonstrated conservation of the key interaction features…
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