Modeling of cancer drugs on the route jak-stat in cancer stem cells

Farzaneh Salmani,1,* Mohsen masoumian,2 Masoud homayouni-tabrizi,3

1. MSc student of Shahid Beheshti University of Medical Sciences, Department of Clinical Biochemistry
2. MSc student of Shahid Beheshti University of Medical Sciences, Department of Clinical Biochemistry
3. Azad University of Mashhad, Department of Biochemistry - Biophysics

Abstract


Introduction

Abstract jak/stat pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. jak activation stimulates cell proliferation, differentiation, cell migration and apoptosis (1, 2). in mammals, there are seven stat genes, stat1, stat2, stat3, stat4, stat5a, stat5b, and stat6. stat3 is broadly studied because of its many functions in animal cell growth regulation, and inflammation. activation of stat3 occurs in many solid and hematologic tumors and is correlated with growth stimulation and anti-apoptotic effects in malignancies (3). hence, the inhibition of stat3 is an effective and novel way to overcome crosstalk- mediated activation of this transcription factor and to prevent tumor cell growth. natural products such as sta-21 (4) as well as synthetic inhibitors, such as stattic (5) have been studied in cancer cell lines and in tumor animal models in order to develop new approaches to cancer chemotherapy. in this paper, we aimed to analyze functional regions of stat3, to present homology models of this protein. in addition, eight different stat3 inhibitors that are currently being investigated in other studies were docked to this protein. finally, we assessed the interaction between modeled stat3 and dna sequences.

Methods

Sequence 644805.1 in ncbi was blasted based on proteins in the pdb. if the results of blast, seven structures (with the pdb codes 4e68-a, 1bg1-a, 3cwg-a, 1yvl-a, 1bf5-a, 4zia-a and 1y1u-a) that have more similar homology with this protein were selected. primary homology models of stat3 were created with a modeler, based on these seven structures. then loop regions of modeled stat3 were improved by moe software and then, were optimized by hyperchem software. to confirm modeling accuracy, prosa-website was used. final modeled structure was valid and was ready to use in docking process. the chemical compounds mentioned, were constructed by marvinsketch software and compounds stattic and sta-21 were obtained from from pubchem. all compounds were minimized by hyperchem software. docking was performed by autodock 4.2 program. ligplot software was used to investigate the interactions. autodock software was used to estimate binding free energy and ligand-protein interaction effects.

Results

Docking results showed that, of these drugs, the drug ins354 high affinity to amino acids lys574 and arg 688 to sh2 domain and sta-21 for dna binding domain with lys574 and glu616. energy binding for ins354 and sta-21 was respectively -8.29 and -7.98.

Conclusion

This energy binding indicates a high binding affinity to the protein drug. therefore, this protein is inhibited at present of ins354 and sta-21.

Keywords

Stat3 protein، homology, docking