Introduction: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Finding a suitable drug target for newly synthesized compounds remain a major bottle neck in current high throughout medicinal chemistry era. Aim:To effectively synthesize di substituted thiadiazole com pounds and demonstrate drug target identification using an in silico pharmacophore probing approach. Moreover, we also aim to validate the suitability of identified drug target. Materials and Methods:A costeffective and environmental friendly chemical synthesis scheme for production of di substituted thiadiazole compounds was employed. Target identification was conducted by Pharmmapper software. Validation was accomplished by performing molecular docking and further Molecular Hydrophobic Potential (MHP) analysis.Results: Pharmacophore probing base approach identified hepatocyte growth factor receptor (cMet) as a suitable biological target for newly synthesized compounds. Binding free energy values indicate that compound 4b, 4e, 4g and 4h has tremendous potential to be further used as lead compound to design selective inhibitors of cMet receptor. MHP data from current study supports the possibility that hydrophobic contacts might act as major factor stabilizing thiadiazole cMet complex. Moreover, in silico observations of current study are in absolute accordance with previously described in vitro and crystallographic analysis. Conclusion:We demonstrate that thiadiazole compounds synthesized in current investigation has high potential to act in modulation of hepatocyte growth factor receptor (cMet) activity and thereby act as putative therapeutic agent in cancer therapy.[Table/ Fig-1]: Schematic representation of methodology adopted in synthesis of novel thiadiazole derivatives in current study.
Selenoproteins are a group of proteins which contain selenocysteine (Sec or U) in their primary structure. Selenoproteins play a critical role in antioxidant defense, hormone metabolism, immune responses and muscle development. The selenoprotein H (SELENOH) is essential in the regulation of gene expression in response to redox status and antioxidant defense. It has Sec residue located in conserved CXXU motif similar to other selenoproteins. However, exact biological function of Sec residue in SELENOH is not known in detail. Therefore, it is essential to understand the structural and functional role of Sec in SELENOH. In the present study, homology modelling and MD simulation were performed to understand the role of Sec residue in SELENOH. The modelled 3D structure of wild-SELENOH along with two mutants (Mut-UC and Mut-CC) was subjected to MD simulation. Based on simulation results, we demonstrate that wild-SELENOH structure is dynamically stabilized by network of intramolecular hydrogen bonding and internal residue contacts facilitated by Sec residue. In contrast, notable differences have been observed in residue contacts and stability in other two mutant structures. Additionally, docking studies revealed that PRGRKRK motif of wild-SELENOH interacts with HSE and STRE of DNA molecule as observed experimentally. Similar to earlier reports, our sequence analysis study pinpoints conserved PRGRKRK motif present in SELENOH perform dual role as AT-hook motif and NLS. Overall, the obtained results clearly illustrate Sec residue plays an important role to restore functionally active conformation of SELENOH. The present study broadened our current understanding regarding the role of selenocysteine in protein structure and function.
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