Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments. (10th December 2015)

• Record Type: Journal Article
• Authors: Bottegoni, Giovanni; Veronesi, Marina; Bisignano, Paola; Kacker, Puneet; Favia, Angelo D.; Cavalli, Andrea
• Is Part Of: ChemMedChem. Volume 11:Number 12(2016)
• Page Start: 1259
• Page End: 1263
• Publication Date: 2015-12-10
• Subjects: BACE-1 -- GSK-3β -- multitarget-directed ligands -- polypharmacology -- virtual screening; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500521
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: In this study, we report on a virtual ligand screening protocol optimized to identify fragments endowed with activity at multiple targets. Thanks to this protocol, we were able to identify a fragment that displays activity in the low‐micromolar range at both β‐secretase 1 (BACE‐1) and glycogen synthase kinase 3β (GSK‐3β). These two structurally and physiologically unrelated enzymes likely contribute, through different pathways, to the onset of Alzheimer′s disease (AD). Therefore, their simultaneous inhibition holds great potential in exerting a profound effect on AD. In perspective, the strategy outlined herein can be adapted to other target combinations. Abstract : Multitasking for memory : Classical virtual ligand screening protocols can be efficiently adapted to work with fragments within the framework of polypharmacology. Herein we report the in silico discovery of a dual inhibitor of β‐secretase 1 and glycogen synthase kinase 3β, highlighting a new and promising approach in the treatment of Alzheimer′s disease.