Molecular docking studies on inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with amino acids

Stat3 is a mammalian transcription factor which regulates various genes involved in cell growth, proliferation, cell survival andother biological processes. Its constitutive activation promotes dysregulated growth, survival and immune responses whichcontribute to tumor progression and carcinogenesis. Inhibition of Stat3 dimerization which prevents its binding to DNA is arational strategy that could be translated to potential therapeutic applications. The present computational study provides insightsinto the inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with amino acids. The involvement ofresidues like LYS-591, ARG-609, SER-611, GLU-612, SER-613, SER-636 and VAL-637 seems to play an important role in binding ofcurcumin natural derivatives and its amino acids conjugates with Src Homology (SH2) domain of Stat3 monomer.Demethoxycurcumin followed by hexahydrocurcuminol were predicted to be the most potent inhibitors amongst all the curcuminnatural derivatives and known inhibitors (FLLL32, Sta21 and Stattic). Curcumin-proline conjugate (1,7-Bis(4-O-L-prolinoyl-3-methoxyphenyl)-1,4,6-heptatriene-5-ol-3-one) was predicted to be the most potent inhibitor of Stat3 dimerization amongst thecurcumin-amino acid conjugates and known peptide based inhibitor (Phpr-pTYR-LEU-cis-3,4-methanoPRO-GLN-NHBn).