A pharmacological chaperone for human N-acetylgalactosamine-6-sulfate sulfatase enzyme: an in-silico analysis

Deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produces the mucopolysaccharidosis type IV A (MPS IV A, Morquio syndrome type A disease), leading to the accumulation of keratan sulfate and chondroitin-6-sulfate within the lysosome. The use of pharmacological chaperones represents an alternative for the treatment of lysosomal disease, which has not been evaluated for MPS IV A. Here, we describe the modification of the 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc), a pharmacological chaperone previously evaluated for α-N-acetylgalactosaminidase (α-NAGAL), by adding the sulfate group at position 6 (DGJNAc-6Sulfate). Protein-ligand interactions, affinity, and specificity for DGJ, DGJNAc and DGJNAc-6Sulfate were evaluated through computational molecular docking (CMD) for both α-NAGAL and GALNS. α-NAGAL has more affinity for DGJNAc that for DGJ, which agrees with in-vitro reports. α-NAGAL showed lower affinity for DGJNAc-6Sulfate than that of DGJNAc (-82.880 kJ/mol VS -121.086 kJ/mol, respectively), showing that addition of sulfate group might increase specificity of PC for GALNS. Likewise, GALNS has lower affinity energy for DGJNAc-6Sulfate than for DGJNAc (-125.730 vs. -103.107 kJ/mol, respectively), suggesting that addition of sulfate group increase the affinity of DGJNAc for GALNS. Furthermore, DGJNAc-6Sulfate showed similar interactions at the active cavity to those of the natural GALNS ligands, as well as higher affinity than natural GALNS ligands. Although in-vitro and in-vivo validation are still needed, we propose DGJNAc-6Sulfate as a feasible pharmacological chaperone for a Morquio syndrome type A therapy, which could be further modified for the development of pharmacological chaperones for other human sulfatases.