Structure-based mimicking of hydroxylated biphenyl congeners (OHPCBs) for human transthyretin, an important enzyme of thyroid hormone system

In humans, transthyretin (hTTR) is a plasma protein act as a transporter of thyroxine (T4) in the blood. Polychlorinated biphenyls (PCBs) are used in coolants, transformers, plasticizers, and pesticide extenders, etc. due to their physical properties, chemical stability, and dielectric properties. Cytochrome P450 can oxidize the PCBs into hydroxylated PCBs (OHPCBs) which can further interact with hTTR results in hepatoxicity, loss of metabolic rate, memory problems, and neurotoxicity. Molecular docking results show that OHPCBs bind at the active site of hTTR with a more binding affinity as compared to T4. Further, molecular dynamics simulation has been done to confirm the stability of hTTR-OHPCBs complexes. Several analysis parameters like RMSD, RMSF, Rg, SASA, hydrogen bonds numbers, PCA, and FEL revealed that binding of OHPCBs with hTTR results in the formation of stable hTTR-OHPCBs complexes. Individual residues decomposition analysis confirms that Lys15, Leu17, Ala108, Ala109, Leu110, Ser117, and Thr119 of hTTR plays a major role in the binding of OHPCBs to form the lower energy hTTR-OHPCBs complexes. Molecular docking and simulations results emphasize that OHPCBs can efficiently bind at the active site of hTTR, which further leads to inhibition of transportation of T4 in human blood. [Display omitted] •Hydroxylated polychlorinated biphenyls (OHPCBs) can intract with human transthyretin (hTTR).•Molecular docking results showed that OHPCBs has a higher binding affinity as compared to thyroxine (T4).•Molecular dynamics simulation analysis confers the stability of hTTR-OHPCBs complex.•Molecular docking and simulation infer that OHPCBs can mimic the T4 and will block the transportation of T4 in human blood.