title: An improved model for fragment-based lead generation at AstraZeneca.
abstract: Modest success rates in fragment-based lead generation (FBLG) projects at AstraZeneca (AZ) prompted operational changes to improve performance. In this review, we summarize these changes, emphasizing the construction and composition of the AZ fragment library, screening practices and working model. We describe the profiles of the screening method for specific fragment subsets and statistically assess our ability to follow up on fragment hits through near-neighbor selection. Performance analysis of our second-generation fragment library (FL2) in screening campaigns illustrates the complementary nature of flat and 3D fragments in exploring protein-binding pockets and highlights our ability to deliver fragment hits using multiple screening techniques for various target classes. The new model has had profound impact on the successful delivery of lead series to drug discovery projects.
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: nathan@rodintherapeutics.com.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fuller
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. Electronic address: loredana.spadola@astrazeneca.com.
authors.forename: Loredana
authors.initials: L
authors.lastname: Spadola
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cowen
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Patel
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Schönherr
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McKenzie
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, Pepparedsleden 1, Mölndal 431 83, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Edfeldt
authors.affiliation: AstraZeneca Oncology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Al
authors.initials: A
authors.lastname: Rabow
authors.affiliation: AstraZeneca, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Goodnow
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D004345:Drug Industry; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries