Vol. 6, Issue 2, Part B (2024)

Thyroid-related disorders necessitate the discovery of novel therapeutic agents targeting key proteins involved in thyroid hormone synthesis and regulation. In this study, we performed molecular docking of designed heterocyclic compounds with two target proteins, PDB 5HPW and PDB 1XZX, to evaluate their potential inhibitory effects. Protein structures were retrieved from the RCSB Protein Data Bank and pre-processed using Chimera, followed by energy minimization to refine their geometry. Ligand structures were drawn in ACD Sketch and optimized using MM2 energy minimization in ACD/ChemSketch. Molecular docking was conducted using iGEMDOCK and AutoDock Vina, with docking scores assessed based on binding affinities and protein-ligand interactions. Docking results indicated that several compounds, particularly 13h, 14h and 7h, exhibited significant binding affinities. Compound 13h demonstrated strong hydrogen bonding with Met 310 and van der Waals interactions with HIS 435, MET 313 and ILE 276 on PDB 1XZX (-11.1 kcal/mol), along with sigma-pi interactions. Compound 7h exhibited the highest binding affinity (-110.4 kcal/mol) using iGEMDOCK. Interestingly, compounds 7h to 10h were highly active on 5HPW but showed limited interactions with 1XZX. Certain compounds (20h-25h and 32h) failed to dock properly in both software tools, suggesting poor compatibility with the active site. These findings highlight the potential of selected heterocyclic compounds as inhibitors of thyroid-related proteins. The study provides insights into structure-activity relationships and lays the foundation for further experimental validation to explore their therapeutic efficacy in managing thyroid disorders.