title: High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits.
abstract: Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schiebel
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Krimmer
authors.affiliation: Helmholtz-Zentrum Berlin für Materialien und Energie, HZB, BESSY II, Abteilung Makromolekulare Kristallographie, Albert-Einstein-Straße 15, 12489 Berlin, Germany.
authors.forename: Karine
authors.initials: K
authors.lastname: Röwer
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Knörlein
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Park
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stieler
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Frederik R
authors.initials: FR
authors.lastname: Ehrmann
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Kan
authors.initials: K
authors.lastname: Fu
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Nedyalka
authors.initials: N
authors.lastname: Radeva
authors.affiliation: Helmholtz-Zentrum Berlin für Materialien und Energie, HZB, BESSY II, Abteilung Makromolekulare Kristallographie, Albert-Einstein-Straße 15, 12489 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Krug
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany; Helmholtz-Zentrum Berlin für Materialien und Energie, HZB, BESSY II, Abteilung Makromolekulare Kristallographie, Albert-Einstein-Straße 15, 12489 Berlin, Germany.
authors.forename: Franziska U
authors.initials: FU
authors.lastname: Huschmann
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Glöckner
authors.affiliation: Helmholtz-Zentrum Berlin für Materialien und Energie, HZB, BESSY II, Abteilung Makromolekulare Kristallographie, Albert-Einstein-Straße 15, 12489 Berlin, Germany.
authors.forename: Manfred S
authors.initials: MS
authors.lastname: Weiss
authors.affiliation: Helmholtz-Zentrum Berlin für Materialien und Energie, HZB, BESSY II, Abteilung Makromolekulare Kristallographie, Albert-Einstein-Straße 15, 12489 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Mueller
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.affiliation: Institute for Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany. Electronic address: heinea@mailer.uni-marburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
mesh_terms: D018360:Crystallography, X-Ray / Q000379:methods / Q000706:statistics & numerical data*; D066264:Datasets as Topic; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D054852:Small Molecule Libraries / Q000737:chemistry*; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D054852:Small Molecule Libraries; D014867:Water