title: Discovery of a novel class of reversible non-peptide caspase inhibitors via a structure-based approach.
abstract: In this paper, we report a simple structure-based iterative optimizations (SUBITO) strategy to identify and optimize new protein ligands and inhibitors. The approach is based on a combination of NMR-based screening and computational docking methods and enabled the identification of novel chemical leads among hundreds of thousands of commercially available compounds by screening only a few hundred compounds from a scaffold library followed by iterative screening steps where only few dozen compounds are tested. As an application, we report on the discovery of a novel class of non-peptide reversible caspase inhibitors, with IC(50) values in the low micromolar range.
authors.affiliation: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fattorusso
authors.forename: Dawoon
authors.initials: D
authors.lastname: Jung
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Crowell
authors.forename: Martino
authors.initials: M
authors.lastname: Forino
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry*; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry*; D004146:Dioxanes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
chemical_list: D061945:Caspase Inhibitors; D003374:Coumarins; D004146:Dioxanes; D009842:Oligopeptides; D013844:Thiazoles; C499146:acetyl-isoleucyl-glutamyl-threonyl-aspartyl-7-amino-4-trifluoromethylcoumarin; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases