Computational Prediction of Structure−Activity Relationships for the Binding of Aminocyclitols to β-Glucocerebrosidase

• DOI: 10.1021/ci100453a
• Publication Date: 2011-03-08T15:03:58Z
• Authors: Lucía Díaz; Jordi Bujons; Antonio Delgado; Hugo Gutiérrez-de...; Johan Åqvist
• Keywords: Binding affinities; Affinities; Docking (animal); Molecular model

Glucocerebrosidase (GCase, acid β-Glucosidase) hydrolyzes the sphingolipid glucosylceramide into glucose and ceramide. Mutations in this enzyme lead to a lipid metabolism disorder known as Gaucher disease. The design of competitive inhibitors GCase is promising field research for pharmacological chaperones new therapeutic agents. Using series recently reported molecules with experimental binding affinities nanomolar micromolar range, we here report an extensive theoretical analysis their mode. On basis molecular docking, dynamics, free energy calculations using linear interaction method (LIE), provide details on interactions supporting ligand different families compounds. applicability other computational approaches, such COMBINE methodology, also investigated. results show robustness standard parametrization LIE method, which reproduces mean unsigned error 0.7 kcal/mol. Several structure−activity relationships are established models provided, including identification hot spot residues site. derived envisaged important tools ligand-design programs inhibitors.