Investigation of Mutant GFAP Protein Associated with Alexander Disease and its Therapeutic Intervention: Structure Based Drug Design Approach
Systems Biology approach involves integration of experimental and computational research to understand complex biological systems. Alexander's Disease (AxD) was first described by W. S. Alexander in 1949, and is a rare, but often fatal neurological disorder that has been divided into three subtypes based on the age of onset: the infantile, juvenile and adult forms that are shown to be caused by mutations in the gfap gene. The infantile form, with onset between birth and about two years of age, is currently the most common form of the disease. The characteristic neuropathological feature of all forms of AxD is the presence of Rosenthal fibers. In present study, the mutant GFAP protein associated with AxD was investigated by predicting the structure of wild type and mutant GFAP protein. It was found that due to the reported single point mutation, the mutant protein adopted a left handed α-helix structure in sharp contrast to the predicted right handed α-helix of the wt GFAP indicating large conformational change which may be the cause of aggregation of GFAP forming Rosenthal Fibers. In the absence of any commercially available drug to alleviate the symptoms of AxD, the therapeutic intervention of mutant GFAP protein was done using structure based drug design approach. The drug dibutyryl cyclic AMP identified through data mining from STITCH 4.0 was found to be toxic and therefore its structural analogs were generated using GAUSSIAN 09. Each of the 20 structural analogs of dbcAMP were docked with mutant GFAP using Discovery Studio 2.5 and analysed for their toxicity potential using OSIRIS Property Explorer. Three structural analogs i.e. DBCM12, DBCM17 and DBCM20 were found to have favourable docking, druglikeness and did not pose any toxicity risk. These structural analogs identified may be further analysed for therapeutic intervention of AxD by their role in prevention of aggregation of mutant GFAP.
Kitano H. (2002). Systems Biology: A Brief Overview, Science, 295, 1662-664.
Messing A., Brenner, M., Feany, M. B., Nedergaard, M., & Goldman, J. E. (2012). Alexander Disease. The Journal of Neuroscience, 32(15), 5017–5023.
Sawaishi Y. (2009). Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev, 31(7), 493–8.
Diana Rodriguez, Fernande Gauthier, Enrico Bertini, Michael Brenner, Sylvie N'guyen, Cyril Goizet, Antoinette Gelot, Robert Surtees, Jean-Michel Pedespan, Xavier Hernandorena, Monica Troncoso, Graziela Uziel, Albee Messing, Gérard Ponsot, Danielle Pham-Dinh, André Dautigny, and Odile Boespflug-Tanguy (2001). Infantile Alexander Disease: Spectrum of gfap Mutations and Genotype-Phenotype Correlation. American Journal of Human Genetics, 69(5), 1134–1140.
Tai-Seung Nam, Jin Hee Kim, Chi-Hsuan Chang, Woong Yoon, Yoon Seok Jung, Sa-Yoon Kang, Boo Ahn Shin, Ming-Der Perng, Seok-Yong Choi, and Myeong-Kyu Kim (2015). Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease. European Journal of Human Genetics, 23(1), 72–78.
Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K,Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A,Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A. (2011). GFAP Mutations, Age at Onset, and Clinical Subtypes in Alexander Disease. Neurology, 63(13), 1287–1294.
Messing A, LaPash Daniels CM, Hagemann TL. (2013). Strategies for Treatment in Alexander Disease. Neurotherapeutics, 7(4), 507–515.
Wu S, Zhang Y. (2007). LOMETS: A local meta-threading-server for protein structure prediction. Nucleic Acids Research, 35(10), 3375–3382.
Lüthy R, Bowie JU, Eisenberg D. (1992). Assessment of protein models with three-dimensional profiles. Nature, 356(6364), 83-85.
Guex N, Peitsch MC. (1997). SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis, 18(15), 2714-2723.
Sander T, Freyss J, von Korff M, Reich JR, Rufener C. (2009). OSIRIS, an entirely in-house developed drug discovery informatics system. J Chem Inf Model, 49(2), 232-46.
Hehre WJ, Stewart RF and Pople JA. (1969). Self-Consistent Molecular Orbital Methods: Use of Gaussian expansions of Slater-type atomic orbitals. J. Chem. Phys., 51(6), 2657-64.
Montes M, Miteva MA, Villoutreix BO. Krammer, A. (2007). Structure-based virtual ligand screening with LigandFit: Pose prediction and enrichment of compound collections. Proteins, 68(3), 712-25.
Quinlan RA, Brenner M, Goldman JE, Messing A. (2007). GFAP and Its Role in Alexander Disease. Experimental cell research, 313(10), 2077-87.
Yang, Jianyi, and Yang Zhang. (2015). Protein Structure and Function Prediction Using I-TASSER. Current protocols in bioinformatics, 52, 5.8.1–5.815.
Videnovic, A. (2013). Treatment of huntington disease. Curr Treat Options Neurol., 15(4), 424-438.
Schwarze-Eicker K, Keyvani K, Görtz N, Westaway D, Sachser N, Paulus W. (2005). Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging, 26(8), 1177-1182.
Peng R, Zhao GX, Li J, Zhang Y, Shen XZ, Wang JY, Sun JY. (2016) Auphen and dibutyryl cAMP suppress growth of hepatocellular carcinoma by regulating expression of aquaporins 3 and 9 in vivo. World J Gastroenterol, 22(12), 3341-3354.
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