Pyridinone Derivatives as Potential Transthyretin Binders: A Computational Discovery for Heart Failure

ABSTRACT Congestive heart failure driven by transthyretin amyloid cardiomyopathy (ATTR‐CM) remains a significant therapeutic challenge. In this study, we evaluated four pyridinone derivatives, namely ( R ‐methyl)phenyl 2‐hydroxybenzoate ( 1 ), R ‐formaldehyde ( 2 ), R' ‐formaldehyde ( 3 ), R ‐methane ( 4 ) ( R = benzyl‐6‐methyl‐2‐oxo‐4‐phenyl‐1,2‐dihydropyridin‐3‐ylamino, R' = 4‐fluorobenzyl‐6‐methyl‐2‐oxo‐4‐phenyl‐1,2‐dihydropyridin‐3‐ylamino), as potential transthyretin (TTR) stabilizers. Using Hirshfeld surface analysis, DFT calculations and molecular docking simulations against three distinct TTR crystal structures (1GKO, 8PM9 and 4WNS), we characterized crystal packing motifs, electronic properties and binding interactions within the TTR thyroxine‐binding site. All four compounds exhibited predicted binding energies superior to the structural comparators Amrinone and Milrinone, and comparable to the therapeutic benchmark Tafamidis. The docking analysis revealed that compound 1 demonstrates the strongest and most conformationally resilient binding across all structures, while compound 4 achieves the most balanced profile with the highest ligand efficiency and fit quality, alongside acceptable lipophility. However, compound 1 exhibits concerning lipophility and poor ligand efficiency, indicating the need for optimization. In silico ADMET profiling revealed favorable drug‐like properties for compounds 2–4 , though potential neurotoxicity was noted across the series. These computational findings identify compounds 1–4 as promising TTR binders, with compound 4 emerging as the most balanced lead candidate, warranting experimental validation in TTR tetramer stabilization assays.