Rational Design and Molecular Docking Studies of Novel Dual-Thionamide Antithyroid Agent with Enhanced Thyroid Peroxidase Inhibition Through Bidentate Heme Coordination

Background: Hyperthyroidism management remains constrained by limited pharmacological innovation, with thionamide therapy exhibiting suboptimal remission rates and significant adverse effects. Thyroid peroxidase (TPO) inhibition through conventional monodentate heme coordination demonstrates transient efficacy, necessitating novel therapeutic approaches. Objective: To rationally design and computationally validate a dual-thionamide antithyroid agent with enhanced TPO inhibitory potency through bidentate heme coordination. Methods: Comprehensive computational workflow integrating de novo scaffold generation, quantum mechanical optimization (B3LYP/6-31G(d,p)), molecular docking (AutoDock Vina), 200 ns molecular dynamics simulations (GROMACS/AMBER99SB-ILDN), MM-PBSA binding free energy calculations, and structure-activity relationship analysis across 15 structural analogs was employed to design and characterize a novel antithyroid molecule designated Thiazolthiouracil . Results: Thiazolthiouracil exhibited superior binding affinity (-9.6 kcal/mol) compared to methimazole (-7.3 kcal/mol), propylthiouracil (-6.8 kcal/mol), and carbimazole (-7.5 kcal/mol), representing 32-41% enhancement (p<0.001). Bidentate Fe-S coordination geometry (Fe-S₁: 2.32 Å, Fe-S₂: 2.38 Å, angle: 98.7°) demonstrated 97.2% occupancy throughout MD simulations versus 68-71% for conventional agents. MM-PBSA calculations revealed ΔG_binding = -45.8±3.2 kcal/mol, 34-54% superior to clinical comparators. The mechanism involves dual-site heme occupation inducing catalytically incompetent low-spin Fe(III) configuration, extensive hydrogen bonding network stabilization, and 93.5% active site occlusion (SASA reduction: 12.3→0.8 Ų). Conclusion: Thiazolthiouracil represents a novel antithyroid molecule computationally validated with predicted superior and sustained TPO inhibition through persistent bidentate coordination, warranting experimental validation and clinical development.