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Molecular docking studies on inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with
1Computational Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781039, Assam, India.
Abstract:
Stat3 is a mammalian transcription factor which regulates various genes involved in cell growth, proliferation, cell survival and other biological processes. Its constitutive activation promotes dysregulated growth, survival and immune responses which contribute to tumor progression and carcinogenesis. Inhibition of Stat3 dimerization which prevents its binding to DNA is a rational strategy that could be translated to potential therapeutic applications. The present computational study provides insights into the inhibition of Stat3 dimerization by curcumin natural derivatives and its conjugates with amino acids. The involvement of residues like LYS-591, ARG-609, SER-611, GLU-612, SER-613, SER-636 and VAL-637 seems to play an important role in binding of curcumin 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 curcumin natural 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 the curcumin-amino acid conjugates and known peptide based inhibitor (Phpr-pTYR-LEU-cis-3,4-methanoPRO-GLN-NHBn).
Insights
This study computationally investigated curcumin derivatives and their amino acid conjugates as inhibitors of Signal Transducer and Activator of Transcription 3 (Stat3) dimerization. Demethoxycurcumin and a curcumin-proline conjugate showed the most potent inhibitory effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Signal Transducer and Activator of Transcription 3 (Stat3) is a key transcription factor regulating cell growth and survival.
- Constitutive activation of Stat3 is implicated in tumor progression and carcinogenesis.
- Inhibiting Stat3 dimerization is a promising therapeutic strategy.
Purpose of the Study:
- To computationally explore the potential of curcumin derivatives and their amino acid conjugates in inhibiting Stat3 dimerization.
- To identify potent inhibitors for therapeutic development against Stat3-driven cancers.
Main Methods:
- In silico analysis of molecular interactions between Stat3 monomer (SH2 domain) and various curcumin derivatives/conjugates.
- Comparative evaluation of inhibitory potential against known Stat3 inhibitors (FLLL32, Sta21, Stattic, and a peptide-based inhibitor).
Main Results:
- Specific amino acid residues (LYS-591, ARG-609, SER-611, GLU-612, SER-613, SER-636, VAL-637) are crucial for binding.
- Demethoxycurcumin was identified as the most potent curcumin derivative inhibitor.
- Curcumin-proline conjugate demonstrated superior inhibitory activity among the conjugates.
Conclusions:
- Curcumin derivatives and their amino acid conjugates show significant potential as Stat3 dimerization inhibitors.
- Demethoxycurcumin and curcumin-proline conjugate are promising lead compounds for developing novel cancer therapeutics targeting Stat3.
