In silico identification of pharmacological chaperones for mucopolysaccharidosis type IIIB

Mucopolysaccharidosis type IIIB (MPS IIIB) is a genetic metabolic disease characterized by mutations in the NAGLU gene, which leads to a reduced activity in the enzyme N-alpha-acetylglucosaminidase and its inhability to breakdown heparan sulfate. This pathology causes the built up of heparan sulfate in the lysosomes, especially in the brain, which can produce severe neurological symptoms. Neither enzyme replacement therapy (ERT) nor bone marrow transplants have been shown to be effective in its treatment. A novel approach in the treatment of lysosomal diseases is the use of pharmacological chaperones (PC). These molecules can bind to orthosteric or allosteric sites of the defective enzyme and reduce the energy barriers needed for the mutant protein to adopt a functional folding, thus, preventing its aggregation or degradation through the ubiquitin proteasome system (UPS) or the cellular unfolded protein response (UPR). In this study, we modeled the interaction of natural and artificial substrates within the active cavity of NAGLU, and identified potential allosteric sites. With this information, virtual screening against a database of 11,200 molecules was performed to identify possible PC. The natural substrates of the enzyme elicited interactions with the residues GLU316 and GLU446 of the active site, which had been previously characterized as the main catalytic residues. Among the top 30 molecules obtained from the screening, 5 were able to cross the brain blood barrier according to an in silico prediction, and all of them interacted with the catalytic residues of the active site. The biological activity of some of these potential PC included anti-inflammatory activity and antipsychotic activity, which can also help ameliorate some of the symptoms of the disease. We expect that these results will yield valuable information regarding the possibility of using pharmacological chaperones as treatment not only for MPS IIIB, but for other lysosomal diseases.