The Interaction of Ile-Phe Dipeptide with Phosphatidylinositide 3-Kinase (PI3K): Molecular Dynamics and Molecular Docking Studies

Year 2020, Volume: 5 Issue: 1, 18 - 29, 19.02.2020

Bilge Bicak Yagmur Kokcu Serda Kecel-gunduz Aysen E. Ozel Sevim Akyuz

https://doi.org/10.28978/nesciences.691673

Abstract

Self-assembly of phenylalanine creates Phe fibers which is the characteristic fiber model found in amyloid fibrils linked with various neurodegenerative diseases. L-Isoleucyl-L-Phenylalanine (Ile-Phe) dipeptide is composed of isoleucine and phenylalanine amino acids, having fibrillary structure similar to nanotube forms of the core recognition motif of Alzheimer's β-amyloid polypeptide. The integrated coordination of neuronal responses via the PI3-K / Akt pathway has a significant functional impact on Alzheimer's disease. Exposure to Aβ in neuronal cultures leads to deterioration of PI3-K, Akt and mTOR signaling, which may cause cognitive loss during disease. Modulation of PI3-K, Akt and mTOR signal activity need aim to reduce or eliminate the accumulation of potential neurotoxins. The therapeutic approaches aimed to normalize neuronal responses on these pathways or activation of PI3-kinase have a protective effect against cognitive decline in animal models of Alzheimer disease. This study aims to determine the interaction of PI3-kinase with Ile-Phe dipeptide having amyloid fibril structure by three-dimensional simulation techniques such as molecular dynamics (with the GROMACS program) and molecular docking techniques (Schrodinger Software program).

Keywords

Ile-Phe, Molecular Dynamics, Molecular Docking, ADME

References

• Benet, L. Z., Kroetz, D., Sheiner, L., Hardman, J., & Limbird, L. (1996). Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. Goodman and Gilman’s the pharmacological basis of therapeutics, 3-27.
• Berendsen, H. (1991). Transport properties computed by linear response through weak coupling to a bath. Computer Simulation in Materials Science ,Springer, pp. 139-155
• Bienert, S., Waterhouse, A., de Beer, T. A., Tauriello, G., Studer, G., Bordoli, L., & Schwede, T. (2016). The SWISS-MODEL Repository—new features and functionality. Nucleic acids research, 45(D1), D313-D319.
• Brunet, A., Datta, S. R., & Greenberg, M. E. (2001). Transcription-dependent and-independent control of neuronal survival by the PI3K–Akt signaling pathway. Current opinion in neurobiology, 11(3), 297-305.
• de Groot, N. S., Parella, T., Aviles, F. X., Vendrell, J., & Ventura, S. (2007). Ile-Phe dipeptide self-assembly: clues to amyloid formation. Biophysical journal, 92(5), 1732-1741.
• Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., . . . Perry, J. K. (2004). Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of medicinal chemistry, 47(7), 1739-1749.
• Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., . . . Mainz, D. T. (2006). Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein− ligand complexes. Journal of medicinal chemistry, 49(21), 6177-6196.
• Frisch, M., Trucks, G., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., . . . Petersson, G. (2009). Gaussian 09, revision a. 02, gaussian. Inc., Wallingford, CT, 200. Görbitz, C. H. (2006). The structure of nanotubes formed by diphenylalanine, the core recognition motif of Alzheimer's β-amyloid polypeptide. Chemical communications, 22, 2332-2334.
• Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004). Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of medicinal chemistry, 47(7), 1750-1759.
• Harder, E., Damm, W., Maple, J., Wu, C., Reboul, M., Xiang, J. Y., . . . Knight, J. L. (2015). OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. Journal of chemical theory and computation, 12(1), 281-296.
• Hess, B., Bekker, H., Berendsen, H. J., & Fraaije, J. G. (1997). LINCS: a linear constraint solver for molecular simulations. Journal of computational chemistry, 18(12), 1463-1472.
• Johansen, A., Hansen, H. D., Svarer, C., Lehel, S., Leth-Petersen, S., Kristensen, J. L., ... & Knudsen, G. M. (2018). The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C] Cimbi-36 labeled in two positions. Journal of Cerebral Blood Flow & Metabolism, 38(4), 659-668.
• Kitagishi, Y., Nakanishi, A., Ogura, Y., & Matsuda, S. (2014). Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease. Alzheimer's research & therapy, 6(3), 35.
• Kol, N., Adler-Abramovich, L., Barlam, D., Shneck, R. Z., Gazit, E., & Rousso, I. (2005). Self-assembled peptide nanotubes are uniquely rigid bioinspired supramolecular structures. Nano letters, 5(7), 1343-1346.
• Lexa, K. W., Dolghih, E., & Jacobson, M. P. (2014). A structure-based model for predicting serum albumin binding. PLoS One, 9(4), e93323.
• Parrinello, M., & Rahman, A. (1981). Polymorphic transitions in single crystals: A new molecular dynamics method. Journal of Applied physics, 52(12), 7182-7190.
• Release, S. (2017). 2: QikProp. Schrödinger, LLC: New York, NY, USA.
• Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. Journal of computer-aided molecular design, 27(3), 221-234.
• Smith, P. E., & van Gunsteren, W. F. (1993). The viscosity of SPC and SPC/E water at 277 and 300 K. Chemical physics letters, 215(4), 315-318.
• Sondergaard, C. R., Olsson, M. H., Rostkowski, M., & Jensen, J. H. (2011). Improved treatment of ligands and coupling effects in empirical calculation and rationalization of p K a values. Journal of chemical theory and computation, 7(7), 2284-2295.
• Turkseven, C. H. (2014). Alzheimer Hastalarinin Beyin Ve Iskelet Kas Hucrelerinde Amiloid Beta Toksisitesi Uzerine Huperzin-A’nin Etkileri. M.Sc.Thesis, Mersin University. Turner, P. ,2005, XMGRACE, Version 5.1. 19. Center for Coastal and Land-Margin Research, Oregon Graduate Institute of Science and Technology, Beaverton, OR.
• Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., & Berendsen, H. J. (2005). GROMACS: fast, flexible, and free. Journal of computational chemistry, 26(16), 1701-1718.
• van Gunsteren, W. F., Billeter, S. R., Eising, A. A., Hünenberger, P. H., Krüger, P., Mark, A. E., . . . Tironi, I. G. (1996). Biomolecular simulation: the {GROMOS96} manual and user guide.
• Wodak, S. J., & Janin, J. (1978). Computer analysis of protein-protein interaction. Journal of molecular biology, 124(2), 323-342.
• Wolfe, K. J., & Cyr, D. M. (2011). Amyloid in neurodegenerative diseases: friend or foe?. Paper presented at the Seminars in cell & developmental biology.
• Xu, A. W., Kaelin, C. B., Takeda, K., Akira, S., Schwartz, M. W., & Barsh, G. S. (2005). PI3K integrates the action of insulin and leptin on hypothalamic neurons. The Journal of clinical investigation, 115(4), 951-958.
• Zhang, N., Ayral-Kaloustian, S., Anderson, J. T., Nguyen, T., Das, S., Venkatesan, A. M., . . . Hollander, I. (2010). 5-Ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-α and mTOR for the treatment of breast cancer. Bioorganic & medicinal chemistry letters, 20(12), 3526-3529.