یافته های نوین در علوم زیستی

بررسی اثر مهاری مشتقات جدید ایمیدازولی بر آنزیم سیکلواکسیژناز II با رویکرد محاسباتی

نویسندگان

زینب ملایی 1
لیلا کرمی 1
الهام رضایی 2
گیلدا کریمی 1

1 گروه زیست شناسی سلولی و مولکولی، دانشکده علوم زیستی، دانشگاه خوارزمی، تهران، ایران

2 گروه شیمی دارویی، دانشکده داروسازی، دانشگاه علوم پزشکی شهید بهشتی، تهران، ایران

چکیده
امروزه مشخص شده که ایزوفرم دوم آنزیم COX موسوم به COX-2 با تولید واسطه های التهابی نقش مهمی در التهاب و در بیماری هایی همچون آرتریت روماتوئید و آرتروز دارد. با این هدف طراحی داروهای مهارکننده COX-2 برای درمان التهاب یکی از مهم ترین اهداف محققان است. در این مطالعه با رویکرد in silico، اثر مهاری 3 مشتق جدید ایمیدازولی بر آنزیم COX-2 ارزیابی شد. داکینگ مولکولی با استفاده از Autodock Vina انجام شده و بهترین حالت اتصالی مهارکننده ها با آنزیم به عنوان ورودی شبیه سازی دینامیک مولکولی (MD) مورد استفاده قرار گرفت. MD با استفاده از نرم افزار Gromacs، به مدت 120 نانوثانیه انجام شد. سپس آنالیزهای ساختاری و ترمودینامیکی (تغییرات انرژی آزاد اتصال) و پیشگویی خواص فیزیکوشیمیایی انجام شدند. بر اساس داده های RMSD، ترکیبات در طی شبیه سازی به تعادل خوبی رسیدند و ثبات مطلوبی داشتند. همینطور نمودارهای RMSF نشان دادند که در اثر اتصال مهارکننده ها نوسانات کمپلکس ها کاهش پیدا کرد و رزیدوهای جایگاه فعال کمترین میزان نوسانات را داشتند. آنالیزهای Rg، SASA و DSSP نشان دادند که ساختار پروتئین تغییر چشمگیری نداشته است. همچنین مشخص شد که رزیدوهای Ser 530 وTyr 355 در تشکیل پیوند هیدروژنی نقش موثرتری دارند. بررسی پارامترهای فیزیکوشیمیایی بیانگر رفتار دارویی مناسب مهارکننده ها است. انجام آنالیزهای ساختاری و ترمودینامیکی (با روش MM-PBSA) و نیز مقایسه با داده های آزمایشگاهی IC50 حاکی از تاثیر مهاری مطلوب ترکیب 5b نسبت به سایر ترکیبات بر آنزیم COX-2 است.


کلیدواژه‌ها

التهاب
انرژی آزاد اتصال
داکینگ مولکولی
شبیه سازی دینامیک مولکولی
مهارکننده های COX-2

عنوان مقاله English

Investigating the inhibitory effect of new imidazole derivatives on cyclooxygenase II enzyme with computational approach

نویسندگان English

Zeinab Mollaie 1
Leila Karami 1
Elham Rezaee 2
Gilda Karimi 1
1 Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
2 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
چکیده English

It has been found that the second isoform of COX enzyme known as COX-2 plays an important role in inflammation and rheumatoid arthritis and osteoarthritis. Thus, designing COX-2 inhibitors to treat inflammation is among the most important goals of researchers. In this study, the inhibitory effect of 3 new imidazole derivatives on COX-2 was evaluated by in silico approach. Molecular docking was done using Autodock Vina and the best binding mode of inhibitors was used as input of molecular dynamics (MD) simulation. MD was performed using Gromacs software for 120 ns. Then, structural and thermodynamic analyzes (ΔGbinding) and prediction of physicochemical properties were performed. RMSD data showed the compounds reached a good equilibrium and had favorable stability during simulation. Also, the RMSF showed that due to binding of inhibitors, the fluctuations of complexes decreased and the active site residues had the lowest amount. Rg, SASA and DSSP analysis showed that the protein structure did not change significantly. It was also found that Ser530 and Tyr355 residues play a more effective role in hydrogen bond formation. Physicochemical parameters determined the good drug-likeness properties for all compounds. Structural and thermodynamic analyzes (MM-PBSA) and IC50 data indicate the favorable inhibitory effect of compound 5b.



کلیدواژه‌ها English

binding free energy
COX-2 inhibitors
inflammation
molecular docking
molecular dynamics simulation
Abraham, M.J., Murtola, T., Schulz, R., Páll, S., Smith, J.C., Hess, B. & Lindahl, E. 2015. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1: 19-25.
Ahmed, E.M., Hassan, M.S., El-Malah, A.A. & Kassab, A.E. 2020. New pyridazine derivatives as selective 1COX-2 inhibitors and potential anti-inflammatory agents; design, synthesis and biological evaluation. Bioorganic Chemistry 95: 103497.
Bishop-Bailey, D., Mitchell, J.A. & Warner, T.D. 2006. COX-2 in cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 26: 956-958.
Blobaum, A.L. & Marnett, L.J. 2007. Structural and functional basis of cyclooxygenase inhibition. Journal of Medicinal Chemistry 50: 1425-1441.
Chandrasekharan, N.V. & Simmons, D.L. 2004. The cyclooxygenases. Genome Biology 5: 1-7.
Daiyasu, H. & Toh, H. 2000. Molecular evolution of the myeloperoxidase family. Journal of Molecular Evolution 51: 433-445.
Dileep, K.V., Remya, C., Tintu, I. & Sadasivan, C. 2014. Interactions of selected indole derivatives with COX-2 and their in silico structure modifications towards the development of novel NSAIDs. Journal of Biomolecular Structure and Dynamics 32: 1855-1863.
Duan, Y., Wu, C., Chowdhury, S., Lee, M.C., Xiong, G., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J. & Kollman, P. 2003. A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations. Journal of Computational Chemistry 24: 1999-2012.
El Sayed, M.T., El-Sharief, M.A.S., Zarie, E.S., Morsy, N.M., Elsheakh, A.R., Nayel, M., Voronkov, A., Berishvili, V., Sabry, N., Hassan, G. & Abdel-Aziz, H.A. 2018. Design, synthesis, anti-inflammatory antitumor activities, molecular modeling and molecular dynamics simulations of potential naprosyn® analogs as COX-1 and/or COX-2 inhibitors. Bioorganic Chemistry 76: 188-201.
Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H. & Pedersen, L.G. 1995. A smooth particle mesh Ewald method. The Journal of Chemical Physics 103: 8577-8593.
Gandhi, J., Khera, L., Gaur, N., Paul, C. & Kaul, R. 2017. Role of modulator of inflammation cyclooxygenase-2 in gammaherpesvirus mediated tumorigenesis. Frontiers in Microbiology 8: 538.
Garcia-Aranda, M.I., Gonzalez-Padilla, J.E., Gómez-Castro, C.Z., Gómez-Gómez, Y.M., Rosales-Hernández, M.C., García-Báez, E.V. & Padilla-Martínez, I.I. 2020. Anti-inflammatory effect and inhibition of nitric oxide production by targeting COXs and iNOS enzymes with the 1, 2-diphenylbenzimidazole pharmacophore. Bioorganic & Medicinal Chemistry 28: 115427.
Heidarpoor Saremi, L., Ebrahimi, A. & Lagzian, M. 2021. Identification of new potential cyclooxygenase-2 inhibitors: insight from high throughput virtual screening of 18 million compounds combined with molecular dynamic simulation and quantum mechanics. Journal of Biomolecular Structure and Dynamics 39: 1717-1734.
Hoover, W.G. 1985. Canonical dynamics: Equilibrium phase-space distributions. Physical Review A 31: 1695-1697.
Kapoor, M., Shaw, O. & Appleton, I. 2005. Possible anti-inflammatory role of COX-2-derived prostaglandins: implications for inflammation research. Current Opinion in Investigational Drugs 6: 461-466.
Kiani, A., Rezaee, E. & Tabatabai, S.A. 2018. Novel group of imidazole derivatives as atypical selective cyclooxygenase-2 inhibitors: design, synthesis and biological evaluation. Iranian Journal of Pharmaceutical Research (IJPR) 17: 78-86.
Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46: 3-26.
Mahoney, M.W. & Jorgensen, W.L. 2000. A five-site model for liquid water and the reproduction of the density anomaly by rigid, nonpolarizable potential functions. The Journal of Chemical Physics 112: 8910-8922.
Mbonye, U.R., Yuan, C., Harris, C.E., Sidhu, R.S., Song, I., Arakawa, T. & Smith, W.L. 2008. Two distinct pathways for cyclooxygenase-2 protein degradation. Journal of Biological Chemistry 283: 8611-8623.
Nosé, S. 1984. A unified formulation of the constant temperature molecular dynamics methods. The Journal of Chemical Physics 81: 511-519.
Parrinello, M. & Rahman, A. 1981. Polymorphic transitions in single crystals: A new molecular dynamics method. Journal of Applied Physics 52: 7182-7190.
Patrono, C. 2016. Cardiovascular effects of cyclooxygenase‐2 inhibitors: a mechanistic and clinical perspective. British Journal of Clinical Pharmacology 82: 957-964.
Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham III, T.E., DeBolt, S., Ferguson, D., Seibel, G. & Kollman, P. 1995. AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Computer Physics Communications 91: 1-41.
Phillis, J.W., Horrocks, L.A. & Farooqui, A.A. 2006. Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Research Reviews 52: 201-243.
Rao, P. & Knaus, E.E. 2008. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. Journal of Pharmacy & Pharmaceutical Sciences 11: 81-110.
Rouzer, C.A. & Marnett, L.J. 2009. Cyclooxygenases: structural and functional insights. Journal of Lipid Research 50: 29-34.
Smith, W.L., DeWitt, D.L. & Garavito, R.M. 2000. Cyclooxygenases: structural, cellular, and molecular biology. Annual Review of Biochemistry 69: 145-182.
Sobolewski, C., Cerella, C., Dicato, M., Ghibelli, L. & Diederich, M. 2010. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. International Journal of Cell Biology 2010: 1-21.
Tanabe, T. & Tohnai, N. 2002. Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins & Other Lipid Mediators 68: 95-114.
Trott, O. & Olson, A.J. 2009. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 31: 455-461.
Van Hecken, A., Schwartz, J.I., Depré, M., De Lepeleire, I., Dallob, A., Tanaka, W., Wynants, K., Buntinx, A., Arnout, J., Wong, P., Ebel, D., Gertz, B. & De Schepper, P.J. 2000. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX‐2 versus COX‐1 in healthy volunteers. The Journal of Clinical Pharmacology 40: 1109-1120.
Wang, J., Morin, P., Wang, W. & Kollman, P.A. 2001. Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. Journal of American Chemical Society 123: 5221-5230.
Wu, W., Owino, J., Al-Ostaz, A. & Cai, L. 2014. Applying periodic boundary conditions in finite element analysis. SIMULIA Community Conference. Available from: https://www.3ds.com/newsroom/press-releases/dassault-systemes-opens-2014-simulia-community-conference-highlighting-simulation-age-experience.

  • تاریخ دریافت 18 خرداد 1405
  • تاریخ انتشار 18 خرداد 1405

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