نوع مقاله : مقاله کامل پژوهشی

نویسندگان

1 کارشناس ارشد مهندسی مکانیک، گروه تبدیل انرژی، دانشکده‌ی مهندسی مکانیک، دانشگاه صنعتی شریف، تهران

2 دانشیار، گروه تبدیل انرژی، دانشکده‌ی مهندسی مکانیک، دانشگاه صنعتی شریف، تهران

چکیده

در مطالعات اخیر، PASylation به عنوان یک روش موثر به منظور افزایش نیمه‌عمر داروهای پروتئینی و جایگزینی مناسب برای PEGylation مطرح شده است. در این روش، یک رشته‌ی به مراتب زیست‌سازگارتر و متشکل از پلیمرهای طبیعی، شامل پرولین، آلانین و سرین، که به اختصار به آن رشته‌ی PAS گفته می­شود، برای بهبود مشخصه­های دارو مورد استفاده قرار می­گیرد. در این مقاله، برخی از مشخصه­های داروی G-CSF، نظیر میانگین توانی فاصله‌ی اتمی (RMSD)، حجم هیدرودینامیکی، انرژی کل و میزان آب­دوستی پروتئین مورد بررسی قرار گرفته است. در این راستا، خواص مختلف داروی پروتئینی متصل به رشته‌ی PAS برای سه طول مختلف رشته‌ی مورد نظر (طول­های 210، 420 و 630) مورد بحث و بررسی قرار گرفته است. نتایج به دست آمده بیان‌گر این نکته است که با اتصال رشته‌ی PAS به داروی پروتئینی، حجم هیدرودینامیکی آن افزایش یافته و به واسطه‌ی آن نیمه‌عمر دارو نیز افزایش می­یابد. در نهایت، با در نظر داشتن نتایج به دست آمده در این قسمت، یک توالی اصلاح‌شده برای رشته‌ی PAS مورد نظر پیشنهاد شده است.

کلیدواژه‌ها

موضوعات

عنوان مقاله [English]

Molecular Dynamics Simulation of PASylated G-CSF and Proposing a Modified PAS String Sequence in order to Improve Drug’s Properties

نویسندگان [English]

  • Abbas Gholami 1
  • Amir Shamloo 2

1 MSc Graduated, Mechanical Engineering Department, Sharif University of Technology, Tehran, Iran

2 Associate Professor, Mechanical Engineering Department, Sharif University of Technology, Tehran, Iran

چکیده [English]

PASylation is a new and effective way to increase the half-life of pharmaceutical proteins. This method is an alternative of PEGylaion and uses the natural polymers of Proline, Alanine, and Serine (PAS) amino acids in its structure. In this paper, we have studied the pharmacokinetic properties of PASylated Granulocyte-colony stimulating factor (G-CSF) using Molecular Dynamics (MD) simulation for three different PAS strings length 210, 420 and 630. We studied several important mechanical quantities involving in enhancing half-life time of the conjugated protein like root-mean-square distance (RMSD), hydrodynamic volume, protein total energy and its hydrophilicity and we found out volume expansion, increase in hydrophilicity amount and coil structure in PASylation are main mechanical properties influencing half-life time. We also found out that RMSD will be modified by PASylation while energy level shows erratic behavior examining the mentioned residues properties, we have also offered a modified sequence for PAS string according to the importance of different parameters in PAS string’s function.

کلیدواژه‌ها [English]

  • Pegylation
  • Pasylation
  • G-CSF
  • Half-Life
  • Hydrodynamic Volume
  • Molecular Dynamic
[1]     Duncan, R., Polymer therapeutics: Top 10 selling pharmaceuticals — What next? Journal of Controlled Release, 2014. 190(Supplement C): p. 371-380.
[2]     Pasut, G., Polymers for Protein Conjugation. Polymers, 2014. 6(1): p. 160.
[3]     Harari, D., et al., Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis. The Journal of biological chemistry, 2014. 289(42): p. 29014-29029.
[4]     Leader, B., Q.J. Baca, and D.E. Golan, Protein therapeutics: a summary and pharmacological classification. Nature reviews. Drug discovery, 2008. 7(1): p. 21.
[5]     Abuchowski, A., et al., Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. Journal of Biological Chemistry, 1977. 252(11): p. 3582-6.
[6]     Caliceti, P. and F.M. Veronese, Pharmacokinetic and biodistribution properties of poly(ethylene glycol)–protein conjugates. Advanced Drug Delivery Reviews, 2003. 55(10): p. 1261-1277.
[7]     Webster, R., et al., PEG and PEG conjugates toxicity: towards an understanding of the toxicity of PEG and its relevance to PEGylated biologicals. PEGylated protein drugs: Basic science and clinical applications, 2009: p. 127-146.
[8]     Harris, J.M. and R.B. Chess, Effect of pegylation on pharmaceuticals. Nature reviews. Drug discovery, 2003. 2(3): p. 214.
[9]     Bailon, P., et al., Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon α-2a for the treatment of hepatitis C. Bioconjugate chemistry, 2001. 12(2): p. 195-202.
[10] Schlapschy, M., et al., PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins. Protein Engineering, Design & Selection, 2013. 26(8): p. 489-501.
[11] Veronese, F.M. and G. Pasut, PEGylation, successful approach to drug delivery. Drug discovery today, 2005. 10(21): p. 1451-1458.
[12] Gabizon, A., et al., Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid–PEG conjugates. Advanced drug delivery reviews, 2004. 56(8): p. 1177-1192.
[13] Garay, R.P., et al., Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. 2012, Taylor & Francis.
[14] Greenwald, R.B., et al., Effective drug delivery by PEGylated drug conjugates. Advanced drug delivery reviews, 2003. 55(2): p. 217-250.
[15] Patri, A.K., J.F. Kukowska-Latallo, and J.R. Baker, Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. Advanced drug delivery reviews, 2005. 57(15): p. 2203-2214.
[16] Knop, K., et al., Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angewandte Chemie International Edition, 2010. 49(36): p. 6288-6308.
[17] Carlson, H.A. and J.A. McCammon, Accommodating protein flexibility in computational drug design. Molecular pharmacology, 2000. 57(2): p. 213-218.
[18] Lill, M.A. and M.L. Danielson, Computer-aided drug design platform using PyMOL. Journal of computer-aided molecular design, 2011. 25(1): p. 13-19.
[19] Yang, C., D. Lu, and Z. Liu, How PEGylation enhances the stability and potency of insulin: a molecular dynamics simulation. Biochemistry, 2011. 50(13): p. 2585-2593.
[20] Yang, H. and A.H. Elcock, Association lifetimes of hydrophobic amino acid pairs measured directly from molecular dynamics simulations. Journal of the American Chemical Society, 2003. 125(46): p. 13968-13969.
[21] Eun, C., Molecular dynamics simulations study of hydrophilic and hydrophobic interactions between nanoscale particles. 2010.
[22] Maiti, M., et al., Potential of mean force between hydrophobic solutes in the Jagla model of water and implications for cold denaturation of proteins. The Journal of chemical physics, 2012. 136(4): p. 044512.
[23] Samanta, U., R.P. Bahadur, and P. Chakrabarti, Quantifying the accessible surface area of protein residues in their local environment. Protein engineering, 2002. 15(8): p. 659-667.
[24] Moelbert, S., E. Emberly, and C. Tang, Correlation between sequence hydrophobicity and surface‐exposure pattern of database proteins. Protein Science, 2004. 13(3): p. 752-762.
[25] Moret, M. and G. Zebende, Amino acid hydrophobicity and accessible surface area. Physical Review E, 2007. 75(1): p. 011920.
[26] Aritomi, M., et al., Atomic structure of the GCSF-receptor complex showing a new cytokine-receptor recognition scheme. Nature, 1999. 401(6754): p. 713.