title: Discovery of a novel pyrazole series of group X secreted phospholipase A2 inhibitor (sPLA2X) via fragment based virtual screening.
abstract: The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series.
authors.affiliation: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden. Electronic address: Hongming.chen@astrazeneca.com.
authors.forename: Hongming
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knerr
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Åkerud
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Kenth
authors.initials: K
authors.lastname: Hallberg
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Öster
authors.affiliation: Reagents and Assay Development, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rohman
authors.affiliation: CVMD Innovative Medicines, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Krister
authors.initials: K
authors.lastname: Österlund
authors.affiliation: CVMD Innovative Medicines, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Beisel
authors.affiliation: CVMD Innovative Medicines, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: CVMD Innovative Medicines, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Brengdhal
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sandmark
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bodin
mesh_terms: D001665:Binding Sites; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical; D054509:Group X Phospholipases A2 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism
chemical_list: D064801:Phospholipase A2 Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D054509:Group X Phospholipases A2
keywords: FBLG; Pharmacophore model; Virtual screening; sPLA(2)X inhibitor