Computational Prediction of Deleterious SNPs in the GALNS Gene Implicated in Morquio A Syndrome (MPS IVA)

-acetylgalactosamine-6-sulfatase. The deficiency of this enzyme impairs the degradation of glycosaminoglycans, particularly chondroitin 6-sulfate and keratan sulfate. This research uses a variety of computational techniques for analyzing the GALNS variants mainly causing child death and to provide better healthcare. The variants were collected from research sources, such as PubMed, ResearchGate, and ScienceDirect, along with databases like HGMD, ClinVar, and UniProt. The analysis of the conservation, pathogenicity, and stability of the variations was conducted utilizing algorithms such as ConSurf, PredictSNP, and iStable. Structural analysis was carried out using the PDB databank and PyMOL software. Molecular docking was used to study the interaction of native and variant GALNS proteins with Ezetimibe. GROMACS was used to simulate the behavior of the GALNS protein with variants and Ezetimibe binding in docked complexes for over 100 ns. A total of 345 SNP variants were retrieved, of which D40H, C79R, and C79L variants were identified to be highly deleterious after conservation (75 SNPs), pathogenicity (5 SNPs), and biophysical and stability (3 SNPs) analysis. During docking, the native protein demonstrated a strong binding affinity of -8.54 kcal/mol for the drug. The C79R variant displayed a binding affinity of -8.41 kcal/mol, while the C79L and D40H variants showed affinities of -7.07 and -7.92 kcal/mol, respectively. MD simulations of the native and variant structures showed similar ligand binding flexibility and stability, confirmed by RMSD, RMSF, H-bond, and gyration plots. The increased binding affinity and stability of both complexes suggest that Ezetimibe has comparable therapeutic effects for both the native and variant forms. This work provides detailed structural and dynamic insights into the GALNS protein, paving the way for further research and new treatments for Morquio syndrome A.