title: Discovery of a novel warhead against beta-secretase through fragment-based lead generation.
abstract: Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.
authors.affiliation: Global Structural Chemistry, AstraZeneca R&D, S-431 83 Mölndal, Sweden
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Olsson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
authors.forename: Johanna
authors.initials: J
authors.lastname: Deinum
authors.forename: Philip D
authors.initials: PD
authors.lastname: Edwards
authors.forename: Tonny
authors.initials: T
authors.lastname: de Beer
authors.forename: Rutger H A
authors.initials: RH
authors.lastname: Folmer
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D002460:Cell Line; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; C093270:isocytosine; D003596:Cytosine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase; C509280:BACE1 protein, human