title: Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments.
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.
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, 16163, Genova, Italy. giovanni.bottegoni@iit.it.|BiKi Technologies srl, 16121, Genova, Italy. giovanni.bottegoni@iit.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: PharmaChemistry Facility, Istituto Italiano di Tecnologia, 16163, Genova, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Veronesi
authors.affiliation: Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA, 94158, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Bisignano
authors.affiliation: Drug Repurposing Division, GVK Biosciences Pvt. Ltd., 500076, Hyderabad, India.
authors.forename: Puneet
authors.initials: P
authors.lastname: Kacker
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, 16163, Genova, Italy.
authors.forename: Angelo D
authors.initials: AD
authors.lastname: Favia
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, 16163, Genova, Italy.|FaBit, University of Bologna, 40126, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D064798:Polypharmacology; D017434:Protein Structure, Tertiary; D014227:Triazines / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D014227:Triazines; D000071679:Glycogen Synthase Kinase 3 beta; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: BACE-1; GSK-3β; multitarget-directed ligands; polypharmacology; virtual screening