title: Discovery of novel class 1 phosphatidylinositide 3-kinases (PI3K) fragment inhibitors through structure-based virtual screening.
abstract: The discovery of ligand efficient and lipophilicity efficient fragment inhibitors of class 1 phosphatidylinositide 3-kinases (PI3K) is reported. A fragment version of the AstraZeneca compound bank was docked to a homology model of the PI3K p110β isoform. Interaction-based scoring of the predicted binding poses served to further prioritise the virtual fragment hits. Experimental screening confirmed potency for a total of 18 fragment inhibitors, belonging to five different structural classes.
authors.affiliation: Lead Generation, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Bengt
authors.initials: B
authors.lastname: Kull
authors.forename: Anita
authors.initials: A
authors.lastname: Dellsén
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase