Pyrimethamine-based targeting of HEXA gene mutations in Tay-Sachs disease: a computational analysis

Hexosaminidase-Tay Sachs disease (TSD) is a fatal, progressive neurodegenerative disorder, brought on by an accumulation of GM2 gangliosides that results from a deficiency. Treatment requires the restoration of the brain's HEXA enzyme, but the blood-brain barrier makes this difficult by preventing the preponderance of molecules from entering the brain. This study uses computational approaches analyzing the effects of genetic changes on the HEXA gene. 158 missense mutations were collected from different databases and analyzed using in-silico techniques like Meta-SNP and ConSurf. The mutations (W474C and W485R) were found to be associated with the disease, changing biological properties in areas with strong conservation and declining stability. Previous In vitro cell-based studies using fibroblasts from these patients showed that pyrimethamine can serve as a PC for HEXA and raise intracellular HEXA levels. By applying the treatment to a central part of the brain, the enzyme can travel along its connections and be distributed throughout the entire brain. The binding site of the protein with the ligand pyrimethamine was predicted using molecular docking. The protein's mutational activity on pyrimethamine was determined using molecular dynamics simulations, focusing on the top hit complex structure's resilience, connectivity, and rigidity. The W485R variation showed greater deviation than the native protein and W474C. The study provides insight into the most deleterious mutants, the drug's interaction with protein structures, and its stability with native and selected variants.