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Baghban, Roghayyeh, Farajnia, Safar, Ghasemi, Younes, Mortazavi, Mojtaba, Ghasemali, Samaneh, Zakariazadeh, Mostafa, Zarghami, Nosratollah, Samadi, Nasser. (1400). Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities. سامانه مدیریت نشریات علمی, 46(6), 454-467. doi: 10.30476/ijms.2020.86984.1705
Roghayyeh Baghban; Safar Farajnia; Younes Ghasemi; Mojtaba Mortazavi; Samaneh Ghasemali; Mostafa Zakariazadeh; Nosratollah Zarghami; Nasser Samadi. "Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities". سامانه مدیریت نشریات علمی, 46, 6, 1400, 454-467. doi: 10.30476/ijms.2020.86984.1705
Baghban, Roghayyeh, Farajnia, Safar, Ghasemi, Younes, Mortazavi, Mojtaba, Ghasemali, Samaneh, Zakariazadeh, Mostafa, Zarghami, Nosratollah, Samadi, Nasser. (1400). 'Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities', سامانه مدیریت نشریات علمی, 46(6), pp. 454-467. doi: 10.30476/ijms.2020.86984.1705
Baghban, Roghayyeh, Farajnia, Safar, Ghasemi, Younes, Mortazavi, Mojtaba, Ghasemali, Samaneh, Zakariazadeh, Mostafa, Zarghami, Nosratollah, Samadi, Nasser. Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities. سامانه مدیریت نشریات علمی, 1400; 46(6): 454-467. doi: 10.30476/ijms.2020.86984.1705

Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities

Iranian Journal of Medical Sciences
مقاله 6، دوره 46، شماره 6، بهمن 2021، صفحه 454-467    اصل مقاله (3.48 M)
نوع مقاله: Original Article(s)
شناسه دیجیتال (DOI): 10.30476/ijms.2020.86984.1705
نویسندگان
Roghayyeh Baghban1، 2، 3؛ Safar Farajnia* 4؛ Younes Ghasemi5، 6؛ Mojtaba Mortazavi7؛ Samaneh Ghasemali1؛ Mostafa Zakariazadeh8؛ Nosratollah Zarghami1؛ Nasser Samadi1
1Department of Medical Biotechnology, School of Advanced Medical Science, Tabriz University of Medical Sciences,Tabriz, Iran
2Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3Poostchi Ophthalmology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
4Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
5Pharmaceutical Sciences Research Center, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
6Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
7Department of Biotechnology, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran
8Department of Biology, Payame Noor University, Tehran, Iran
چکیده
Background: Ocriplasmin has been developed for the induction of posterior vitreous detachment in patients with vitreomacular adhesion. At physiological pH, ocriplasmin is susceptible to autolytic and proteolytic degradation, limiting its activity duration. These undesirable properties of ocriplasmin can be reduced by site-directed mutagenesis, so that its enzymatic activities can be augmented. This study aimed to design ocriplasmin variants with improved biological/physicochemical characteristics via bioinformatics tools.
Methods: This study was performed in Tabriz University of Medical Sciences, Tabriz, Iran, 2019. Through site-directed mutagenesis, three ocriplasmin variants were designed. Structural analysis was performed on the wild-type variant and the mutant variants using the Protein Interactions Calculator (PIC) server. The interactions between the S-2403 substrate and the ocriplasmin variants were studied by molecular docking simulations, and binding capability was evaluated by the calculation of free binding energy. The conformational features of protein-substrate complex systems for all the variants were evaluated using molecular dynamic simulations at 100 nanoseconds.
Results: The structural analysis of ocriplasmin revealed that the substitution of threonine for alanine 59 significantly reduced proteolytic activity, while the substitution of glutamic acid for lysine 156 influenced autolytic function. The molecular docking simulation results indicated the appropriate binding of the substrate to the ocriplasmin variants with high-to-low affinities. The binding affinity of the wild-type variant for the substrate was higher than that between the mutant variants and the substrate. Simulation analyses, consisting of the root-mean-square deviation, the root-mean-square fluctuation, and the center-of-mass average distance showed a higher affinity of the substrate for the wild type than for the mutant variants.
Conclusion: The mutational analysis of ocriplasmin revealed that A59T and K156E mutagenesis could be used for the development of a new variant with higher therapeutic efficacy.
کلیدواژه‌ها
Mutagenesis؛ Site-directed؛ Molecular docking simulation؛ Molecular dynamics simulation
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