Abstract
AbstractFabry disease (FD) is a potentially fatal rare genetic disorder that is actuated due to the alpha‐galactosidase (α‐Gal) enzyme's ineptitude to break down a specific type of fat, globotriaosylceramide. At present, there is no effective therapeutics against FD. However, studies have shown 1‐deoxygalactonojirimycin (DGJ) to be a notable pharmacological chaperone against α‐Gal mutants. In this present analysis, theoretical details behind chaperoning ability of DGJ in ameliorating the functional activity of selected α‐Gal mutants were studied. From the literature, 40 missense mutants responsive to DGJ were analysed, T41I and Y216C mutants were screened and studied further. Through MD simulations, structural rigidity and fluctuations were found to be altered in mutants. Moreover, metastable states observed in mutants were concentrated towards stable conformations in the presence of DGJ. Also, simulated thermal unfolding analysis on mutants illustrated a pattern shift of hydrogen bond dilution and rigid cluster decomposition towards that of wild‐type, in the presence of DGJ. Hence, DGJ could alleviate mutant α‐Gal, thereby mitigating the effects of FD.
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