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Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation

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Abstract

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (−)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100 ns using GROMACS software. The inhibitors (−)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.

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Acknowledgements

This work was supported by MHRD-Rashtriya Uchchatar Shiksha Abhiyan (RUSA) 2.0-Bharathiar Cancer and Theragnostic Research Centre (BCTRC), Bharathiar University, Coimbatore, India (BU/RUSA2.0/BCTRC/2020/BCTRC-CT06). The authors also thank B. Satheeswaran, Ph.D. Research Scholar, Bharathiar University for his valuable inputs.

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Authors and Affiliations

  1. Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India

    Suryaa Manoharan & Ekambaram Perumal

  2. Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India

    Ajithkumar Balakrishnan & Vedagiri Hemamalini

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  1. Suryaa Manoharan
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  2. Ajithkumar Balakrishnan
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  3. Vedagiri Hemamalini
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EP and SM conceived the project; SM wrote the entire manuscript. SM, AB, VH and EP performed the experiment.

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Correspondence to Ekambaram Perumal.

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Manoharan, S., Balakrishnan, A., Hemamalini, V. et al. Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation. Mol Divers 27, 1297–1308 (2023). https://doi.org/10.1007/s11030-022-10490-w

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