title: Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies.
abstract: A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment "hits." However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA Current address: Merck, Boston, MA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kutchukian
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Anne Mai
authors.initials: AM
authors.lastname: Wassermann
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Lindvall
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: S Kirk
authors.initials: SK
authors.lastname: Wright
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Ottl
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Jaison
authors.initials: J
authors.lastname: Jacob
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheufler
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Marzinzik
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA Current address: Blueprint Medicines, Cambridge, MA, USA.
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA Peter.Kutchukian@Merck.com Meir.Glick@Novartis.com.
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
mesh_terms: D001499:Bayes Theorem; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries
keywords: fragment; fragment-based screen; naive Bayesian model; privileged substructure