1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
Modeling anticancer drugs on the pathway JAK-STAT in cancer stem cells
Paper ID : 1254-ICB10
Authors:
Zahra Shakibay Senobari *1, Mohsen Masoumian2, Ziba Veisi Malekshahi3, Azadeh Hekmat4
1Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran,
2Department of E-learning in medical science, Virtual University of Medical Sciences, Tehran, Iran
3Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
4Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
Abstract:
In mammals, the JAK / STAT pathway is the major signaling mechanism for a wide range of cytokines and growth factors [1,2]. Many recent studies show that inhibition of STAT3 in various tumor cells has anticancer effects [3]. In this paper, the functional regions of STAT3 were analyzed and structures with PDB codes 4E68-A, 1BG1-A, 3CWG-A, 1YVL-A, 1BF5-A, 4ZIA-A and 1Y1U-A were selected to generate homology models. Water, ligands, and additional chains of these structures were removed using Chimera 1.8 software for modeling with Modeler 9. ProSA-website and Rampage were used to confirm the accuracy of the modeling. STAT Inhibitors FLLL32, HJC0123, STX-0119, LLL12, INS3-54, and Piperlongumin were created using MarvinSketch software and minimized using Hyperchem software. The compounds Stattic and Sta-21 were obtained from PubChem. Molecular docking was performed using AutoDock tools and evaluated after 100 runs. This study showed that despite the explanation of some articles regarding the inhibitory effect of compounds HJC0123, Ins354, Sta-21, and Statiic on the DNA-binding domain, Ins354 appears to bind more strongly to DNA by binding to arg432 and lys574 than the other compounds (-0.26; -8.29). Among these compounds, Statiic appears to bind to both the DNA-binding domain and the SH2 domain with greater stability, inhibiting dermirization and DNA binding. By inhibiting these processes, transcription of the gene is inhibited and the cancer cell can no longer replicate and continue to grow. Since the drugs Ins354 and Sta-21 have the same inhibitory effect, it is expected that taking two drugs at the same time will lead to a competitive situation and the inhibitory effect will not be different from the indicated amount, but may be worse due to the side effects of the two drugs. However, taking one of these two drugs in combination with Statiic may increase the inhibitory effect.
Keywords:
STAT3; SH2 domain; DNA binding domain; Anti cancer drugs; Molecular Docking
Status : Paper Accepted (Poster Presentation)