title: Leveraging structural approaches: applications of NMR-based screening and X-ray crystallography for inhibitor design.
abstract: In the last several years, NMR strategies in drug discovery have evolved from a primarily structural focus to a set of technologies that are non-structural in nature but that have a much greater impact on the identification and optimization of real drug leads. NMR-based screening methods, such as the SHAPES strategy, help rapidly identify good starting points for drug design in a relatively high throughput implementation. The SHAPES method uses simple NMR techniques to detect binding of a limited, but diverse library of low molecular weight, soluble compounds to a potential drug target. SHAPES library compounds are derived largely from molecular frameworks most commonly found in known therapeutic agents. The NMR experiments used in these protocols are based on the well-known NMR techniques, and may be applied to targets with no limitation on molecular weight and no requirement for isotope labeling. Following screening, SHAPES hits may be used to guide virtual screening, synthesis of combinatorial libraries, and bias the first compounds that undergo high throughput screening. Integration of the SHAPES strategy with iterative X-ray crystallographic structure determination can be very useful in deriving an initial structural pharmacophore model and achieving significant in vitro potency in a short time frame. Here, examples are provided of how the combination of NMR SHAPES screening, virtual screening, molecular modeling and X-ray crystallography has led to novel drug scaffolds in several drug discovery programs: JNK3 MAP kinase and the fatty acid binding protein, aP2.
authors.affiliation: Vertex Pharmaceuticals Incorporated, USA. moore@vpharm.com
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moore
authors.forename: Norzehan
authors.initials: N
authors.lastname: Abdul-Manan
authors.forename: Jasna
authors.initials: J
authors.lastname: Fejzo
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.forename: Christopher
authors.initials: C
authors.lastname: Lepre
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Peng
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000648:ultrastructure; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods*; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000648:ultrastructure; D009363:Neoplasm Proteins; D019151:Peptide Library; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000648:ultrastructure; D012110:Reserpine / Q000031:analogs & derivatives*; D018511:Systems Integration
chemical_list: D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D019151:Peptide Library; D004364:Pharmaceutical Preparations; D012110:Reserpine; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C084826:rescinnamine