For the first time, we report novel compounds activating the hydrolysis of natural glucocerebrosidase (GCase) substrate glucosylceramide into ceramide and glucose. Compounds from two distinct chemotypes bind to two distinct sites on GCase: one (32) is located close to the substrate binding site while the other (31) is further away from the catalytic pocket. GlcCer: Glucosylceramide

Abstract

Several novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have distinct chemotypes. Positive allosteric modulators bind to a site on GCase and induce conformational changes, but also induce an equilibrium state between monomer and dimer.