In Silico Evaluation and Structure-Activity-Relationship of Ambroxol analogues against Glucocerebrosidase as potential therapeutics for Lysosomal Storage Diseases

Abstract

Glucocerebrosidase (GCase) plays a critical role in lysosomal function through its hydrolyzing capabilities on glucosylceramide. Deficiency of functional GCase, such as in cases of Gaucher’s disease and GCase-deficient Parkinson’s disease, leads to lysosomal storage disease and toxic accumulation of glucosylceramide. Ambroxol, a repurposed small molecule, has recently demonstrated significant activity as a pharmacological chaperone against misfolded GCase by binding directly to the GCase active site. The principal limitation of ambroxol is its mutation-dependent and relatively modest pharmacological chaperone activity, which results in variable clinical efficacy. In this study, we examined the binding affinity and structure activity relationship of 28 Ambroxol analogs by performing molecular docking experiments. Binding affinity and residue interactions against GCase revealed functional impacts of modifications to linker length, aryl headgroup substitutions, ring rigidity, and the addition of fused ring attachments on the aryl headgroup. Of our 28 molecules, two molecules with fused ring systems and a single-atom linker length demonstrated the most significant improvement in binding affinity, proposing the possibility of improved stabilizing ability in biological systems.