Molecular Docking and In Silico Study of Denileukin Diftitox: Comparison of Wild Type With C۵۱۹S Mutant
محل انتشار: مجله تحقیق در پزشکی مولکولی، دوره: 8، شماره: 2
سال انتشار: 1399
نوع سند: مقاله ژورنالی
زبان: انگلیسی
مشاهده: 72
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شناسه ملی سند علمی:
JR_REMJ-8-2_006
تاریخ نمایه سازی: 20 دی 1402
چکیده مقاله:
Background: Denileukin diftitox (trade name, Ontak) is the first recombinant immunotoxin (IM), in which the binding domain of diphtheria toxin has been replaced by the amino acid sequence of human interleukin-۲ (DT۳۸۹IL-۲) using genetic engineering. Purity, stability, and structural property of the protein are critical factors for the scale-up production of this fusion protein. In this IM, location ۵۱۹ has free cysteine residue that leads to cross S-S bound formation in the refolding process and, as a result, misfolding/aggregation of the protein may occur.
Materials and Methods: To inhibit misfolding/aggregation, we substituted cysteine ۵۱۹ by a serine residue with site-directed mutagenesis, and then the ability of the mutated protein for binding to the IL-۲ receptor was predicted and determined by bioinformatics tools. For this purpose, the sequence of the denileukin diftitox was adopted from Drugbank, and the mentioned substitution applied. Two methods determined the folding of the fusion protein: de novo modeling method (by utilizing the I-TASSER database) and homology modeling method (by using some databases and tools, including Swiss-Model, PHYRE۲, M۴T, ModWeb, RaptorX, and EasyModeller). Finally, the ability of the proteins for binding to the IL-۲ receptor was investigated by pyDock and Zdock docking servers, as well as Hex software.
Results: The result showed that the mutated form (C۵۱۹S) of this protein folds appropriately, and the ΔG of the models, measured by STRUM, showed no significant variation. Also, docking analysis has shown that the protein can efficiently bind to the IL-۲ receptor without any substantial changes in the binding energy.
Conclusion: The present study shows that the suggested mutation of this protein can be an acceptable replacement for denileukin diftitox with a similar affinity and a more proper refolding process.
کلیدواژه ها:
نویسندگان
Mohamad Najarasl
Faculty of Chemistry and Chemical Engineering, Malek Ashtar University of Technology, Iran.
Mehdi Zeinoddini
Faculty of Chemistry and Chemical Engineering, Malek Ashtar University of Technology, Iran.
Ali Reza Saeeidinia
Faculty of Chemistry and Chemical Engineering, Malek Ashtar University of Technology, Iran.
Reza Hasan Sajedi
Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Iran.
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