title: Discovering novel ligands for macromolecules using X-ray crystallographic screening.
abstract: The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification, ultrahigh-throughput screening for lead identification, and structure-based drug design and combinatorial chemistry for lead optimization. A critical juncture in the process is the identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures. Structural information is often consulted to efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography-driven screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment of cancer.
authors.affiliation: Department of Structural Biology, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. vicki.nienaber@abbott.com
authors.forename: V L
authors.initials: VL
authors.lastname: Nienaber
authors.forename: P L
authors.initials: PL
authors.lastname: Richardson
authors.forename: V
authors.initials: V
authors.lastname: Klighofer
authors.forename: J J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: V L
authors.initials: VL
authors.lastname: Giranda
authors.forename: J
authors.initials: J
authors.lastname: Greer
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D046911:Macromolecular Substances; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D046911:Macromolecular Substances; D009281:Naphthalenes; D011804:Quinolines; D014568:Urokinase-Type Plasminogen Activator