Investigation of Mutant GFAP Protein Associated with Alexander Disease and its Therapeutic Intervention: Structure Based Drug Design Approach
Abstract
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.
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