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Fragment-Based NMR Screening in Lead Discovery

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References

  • Becattini B., Sareth S., Zhai D., Crowell K. J., Leone M., Reed J. C. and Pellecchia M. 2004. Targeting apoptosis via chemical design: inhibition of bid-induced cell death by small organic molecules. Chem. Biol. 11, 1107-1117.

    Article  PubMed  CAS  Google Scholar 

  • Boehm H. J., Boehringer M., Bur D., Gmuender H., Huber W., Klaus W., Kostrewa D., Kuehne H., Luebbers T., Meunier-Keller N. and Mueller F. 2000. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J. Med. Chem 43, 2664-2674.

    Article  PubMed  CAS  Google Scholar 

  • Carr R. and Jhoti H. 2002. Structure-based screening of low-affinity compounds. Drug Discovery Today 7, 522-527.

    Article  PubMed  CAS  Google Scholar 

  • Claasen B., Axmann M., Meinecke R. and Meyer B. 2005. Direct observation of ligand binding to membrane proteins in living cells by a saturation transfer double difference (STDD) NMR spectroscopy method shows a significantly higher affinity of integrin alpha(IIb)beta3 in native platelets than in liposomes. J. Am. Chem. Soc. 127, 916-919.

    Article  PubMed  CAS  Google Scholar 

  • Dalvit C., Fogliatto G., Stewart A., Veronesi M. and Stockman B. 2001. WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J. Biomol. NMR. 21, 349-359.

    Article  PubMed  CAS  Google Scholar 

  • Dalvit C., Pevarello P., Tato M., Veronesi M., Vulpetti A. and Sundstrom M. 2000. Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J. Biomol. NMR. 18, 65-68.

    Article  PubMed  CAS  Google Scholar 

  • Fejzo J., Lepre C. A., Peng J. W., Bemis G. W., Ajay, Murcko M. A. and Moore J. M. 1999. The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. Chem. Biol. 6, 755-769.

    Article  PubMed  CAS  Google Scholar 

  • Fejzo J., Lepre C. and Xie X. 2002. Applications of NMR Screening in Drug Discovery. Curr. Top. Med. Chem. 2, 1349-1364.

    Google Scholar 

  • Hajduk P. J., Augeri D. J., Mack J., Mendoza R., Yang J., Betz S. F. and Fesik S. W. 2000a. NMR-based screening of proteins containing 13C-labeled methyl groups. J. Am. Chem. Soc. 122, 7898-7904.

    Article  CAS  Google Scholar 

  • Hajduk P. J., Boyd S., Nettesheim D., Nienaber V., Severin J., Smith R., Davidson D., Rockway T. and Fesik S. W. 2000b. Identification of novel inhibitors of urokinase via NMR-based screening. J. Med. Chem. 43, 3862-3866.

    Article  CAS  Google Scholar 

  • Hajduk P. J., Dinges J., Schkeryantz J. M., Janowick D., Kaminski M., Tufano M., Augeri D. J., Petros A., Nienaber V., Zhong P., et al 1999a. Novel Inhibitors of Erm Methyltransferases from NMR and Parallel Synthesis. J. Med. Chem., 42, 3852-3859.

    Article  CAS  Google Scholar 

  • Hajduk P. J., Gerfin T., Boehlen, J-M, Haberli M., Marek D. and Fesik S. W. 1999b. High-Throughput Nuclear Magnetic Resonance-Based Screening. J. Med. Chem. 42, 2525-2517.

    Google Scholar 

  • Hajduk P. J., Gomtsyan A., Didomenico S., Cowart M., Bayburt E. K., Solomon L., Severin J., Smith R., Walter K., Holzman T. F., et al 2000c. Design of adenosine kinase inhibitors from the NMR-based screening of fragments. J. Med. Chem. 43, 4781-4786.

    Article  CAS  Google Scholar 

  • Hajduk P. J., Meadows R. P. and Fesik S. J. 1999c. NMR-based screening in drug discovery. Quarterly reviews of biophysics 32, 211-240.

    Google Scholar 

  • Huth J. R. and Sun C. 2002. Utility of NMR in lead optimization: fragment-based approaches. Comb. Chem. High Throughput Screen 5, 631-643.

    PubMed  CAS  Google Scholar 

  • Hwang, T-L and Shaka A. J. 1995. Water Suppression That Works. Excitation Sculpting Using Arbitrary Waveforms and Pulsed Field Gradients. J. Magn. Reson. Ser. A. 112, 275-279.

    Article  CAS  Google Scholar 

  • Jahnke W., Blommers M. J., Fernandez C., Zwingelstein C. and Amstutz R. 2005. Strategies for the NMR-Based Identification and Optimization of Allosteric Protein Kinase Inhibitors. Chembiochem. 6, 1607-1610.

    Article  PubMed  CAS  Google Scholar 

  • Jahnke W., Floersheim P., Ostermeier C., Zhang X., Hemmig R., Hurth K. and Uzunov D. P. 2002. NMR reporter screening for the detection of high-affinity ligands. Angew. Chem. Int. Ed. Engl. 41, 3420-3423.

    Article  PubMed  CAS  Google Scholar 

  • Jahnke W., Florsheimer A., Blommers M. J., Paris C. G., Heim J., Nalin C. M. and Perez L. B. 2003. Second-site NMR screening and linker design. Curr. Top. Med. Chem. 3, 69-80.

    Article  PubMed  CAS  Google Scholar 

  • Jahnke W., Perez L. B., Paris G., Strauss A., Fendrich G. and Nalin C. M. 2000. Second-Site NMR Screening with a Spin-Labeled First Ligand. J. Am. Chem. Soc. 122, 7394-7395.

    Article  CAS  Google Scholar 

  • Jahnke W., Rudisser S. and Zurini M. 2001. Spin label enhanced NMR screening. J. Am. Chem. Soc. 123, 3149-3150.

    Article  PubMed  CAS  Google Scholar 

  • Johnson E. C., Feher V. A., Peng J. W., Moore J. M. and Williamson J. R. 2003. Application of NMR SHAPES screening to an RNA target. J. Am. Chem. Soc. 125, 15724-15725.

    Article  PubMed  CAS  Google Scholar 

  • Klaus W. and Senn H. 2003. Strategies for Hit Finding Using NMR. In BioNMR in Drug Research, O. Zerbe, ed. (Weinheim, Wiley-VCH) pp. 417-437.

    Google Scholar 

  • Klein J., Meinecke R., Mayer M. and Meyer B. 1999. Detecting Binding Affinity to Immobilized Receptor Proteins in Compound Libraries by HR-MAS STD NMR. J. Am. Chem. Soc. 121, 5336-5337.

    Article  CAS  Google Scholar 

  • Lepre C. A. 2001. Library Design for NMR-Based Screening. Drug Discov Today 6, 133-140.

    Article  PubMed  CAS  Google Scholar 

  • Lepre C. A. 2002. Strategies for NMR screening and library design. In BioNMR Techniques in Drug Research, O. Zerbe, ed. (Weinheim, Wiley-VCH) pp. 1349-1364.

    Google Scholar 

  • Lepre C. A., Moore J. M. and Peng J. W. 2004. Theory and applications of NMR-based screening in pharmaceutical research. Chem. Rev. 104, 3641-3676.

    Article  PubMed  CAS  Google Scholar 

  • Lepre C. A., Peng J., Fejzo J., Abdul-Manan N., Pocas J., Jacobs M., Xie X. and Moore J. M. 2002. Applications of SHAPES screening in drug discovery. Comb. Chem. High Throughput Screen 5, 583-590.

    Google Scholar 

  • Lesuisse D., Lange G., Deprez P., Benard D., Schoot B., Delettre G., Marquette J. P., Broto P., Jean-Baptiste V., Bichet P., et al 2002. SAR and X-ray. A new approach combining fragment-based screening and rational drug design: application to the discovery of nanomolar inhibitors of Src SH2. J. Med. Chem. 45, 2379-2387.

    Article  PubMed  CAS  Google Scholar 

  • Li D., DeRose E. F. and London R. E. 1999. The inter-ligand Overhauser effect: A powerful new NMR approach for mapping structural relationships of macromolecular ligands. J. Biomol. NMR. 15, 71-76.

    Article  MATH  PubMed  CAS  Google Scholar 

  • Liepinsh E. and Otting G. 1997. Organic solvents identify specific ligand binding sites on protein surfaces. Nat. Biotechnol. 15, 264-268.

    Article  PubMed  CAS  Google Scholar 

  • Lipinski C. A., Lombardo F., Dominy B. W. and Feeny P. J. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 23, 3-25.

    Article  CAS  Google Scholar 

  • Liu G., Szczepankiewicz B. G., Pei Z., Janowick D. A., Xin Z., Hajduk P. J., Abad-Zapatero C., Liang H., Hutchins C. W., Fesik S. W., et al 2003a. Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B. J. Med. Chem. 46, 2093-2103.

    Article  CAS  Google Scholar 

  • Liu G., Xin Z., Liang H., Abad-Zapatero C., Hajduk P. J., Janowick D. A., Szczepankiewicz B. G., Pei Z., Hutchins C. W., Ballaron S. J., et al 2003b. Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands. J. Med. Chem. 46, 3437-3440.

    Article  CAS  Google Scholar 

  • Liu G., Xin Z., Pei Z., Hajduk P. J., Abad-Zapatero C., Hutchins C. W., Zhao H., Lubben T. H., Ballaron S. J., Haasch D. L., et al 2003c. Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J. Med. Chem. 46, 4232-4235.

    Article  CAS  Google Scholar 

  • Lugovskoy A. A., Degterev A. I., Fahmy A. F., Zhou P., Gross J. D., Yuan J. and Wagner G. 2002. A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors. J. Am. Chem. Soc. 124, 1234-1240.

    Article  PubMed  CAS  Google Scholar 

  • Mayer M. and Meyer B. 1999. Characterization of Ligand Binding by Saturation Transfer Difference NMR Spectroscopy. Angew. Chem. Int. Ed. 38, 1784-1788.

    Article  CAS  Google Scholar 

  • McCoy M. A., Senior M. M. and Wyss D. F. 2005. Screening of protein kinases by ATP-STD NMR spectroscopy. J. Am. Chem. Soc. 127, 7978-7979.

    Article  PubMed  CAS  Google Scholar 

  • McCoy M. A. and Wyss D. F. 2000. Alignment of weakly interacting molecules to protein surfaces using simulations of chemical shift perturbations. J. Biomol. NMR. 18, 189-198.

    Article  PubMed  CAS  Google Scholar 

  • McCoy M. A. and Wyss D. F. 2002. Spatial Localization of Ligand Binding Sites from Electron Current Density Surfaces Calculated from NMR Chemical Shift Perturbations. J. Am. Chem. Soc. 124, 11758-11763.

    Article  PubMed  CAS  Google Scholar 

  • Medek A., Hajduk P. J., Mack J. and Fesik S. W. 2000. The Use of Differential Chemical Shifts for Determining the Binding Site Location and Orientation of Protein-Bound Ligands. J. Am. Chem. Soc. 122, 1241-1242.

    Article  CAS  Google Scholar 

  • Meinecke R. and Meyer B. 2001. Determination of the Binding Specificity of an Integral Membrne Protein by Saturation Transfer Difference NMR: RGD Peptide Ligands Binding to Integrin aIIbb3. J. Am. Chem. Soc. 44, 3059-3065.

    CAS  Google Scholar 

  • Moore J. M. 1999. NMR screening in drug discovery. Curr Opin Biotechnol 10, 54-58.

    Article  PubMed  CAS  Google Scholar 

  • Nienaber V. L., Richardson P. L., Klighofer V., Bouska J. J., Giranda V. L. and Greer J. 2000. Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat. Biotechnol. 18, 1105-1108.

    Article  PubMed  CAS  Google Scholar 

  • Oltersdorf T., Elmore S. W., Shoemaker A. R., Armstrong R. C., Augeri D. J., Belli B. A., Bruncko M., Deckwerth T. L., Dinges J., Hajduk P. J., et al 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681.

    Article  PubMed  ADS  CAS  Google Scholar 

  • Park C. M., Sun C., Olejniczak E. T., Wilson A. E., Meadows R. P., Betz S. F., Elmore S. W. and Fesik S. W. 2005. Non-peptidic small molecule inhibitors of XIAP. Bioorg. Med. Chem. Lett. 15, 771-775.

    Article  PubMed  CAS  Google Scholar 

  • Pellecchia M., Meininger D., Dong Q., Chang E., Jack R. and Sem D. S. 2002a. NMR-based structural characterization of large protein-ligand interactions. J. Biomol. NMR 22, 165-173.

    Article  CAS  Google Scholar 

  • Pellecchia M., Sem D. S. and Wuthrich K. 2002b. NMR in drug discovery. Nat. Rev. Drug. Discov. 1, 211-219.

    Article  CAS  Google Scholar 

  • Peng J. W., Moore J. and Abdul-Manan N. 2004. NMR Experiments for Lead Generation in Drug Discovery. Prog. Nucl. Mag. Reson. Spectrosc. 44, 225-256.

    Article  CAS  Google Scholar 

  • Peng J. W., Lepre C. A., Fejzo J., Abdul-Manan N. and Moore J. M. 2001. Nuclear magnetic resonance-based approaches for lead generation in drug discovery. Methods Enzymol 338, 202-230.

    Article  PubMed  CAS  Google Scholar 

  • Roberts G. C. 2000. Applications of NMR in drug discovery. Drug Discov Today 5, 230-240.

    Article  PubMed  CAS  Google Scholar 

  • Ross A., Schlotterbeck G., Klaus W. and Senn H. 2000. Automation of NMR measurements and data evaluation for systematically screening interactions of small molecules with target proteins. J. Biomol. NMR 16, 139-146.

    Article  PubMed  CAS  Google Scholar 

  • Ross A. and Senn H. 2001. Automation of measurements and data evaluation in biomolecular NMR screening. Drug Discovery Today 6, 583-593.

    Article  PubMed  CAS  Google Scholar 

  • Rudisser S. and Jahnke W. 2002. NMR and in silico screening. Comb. Chem. High Throughput Screen 5, 591-603.

    PubMed  CAS  Google Scholar 

  • Shuker S. B., Hajduk P. J., Meadows R. P. and Fesik S. W. 1996. Discovering High-Affinity Ligands for Proteins: SAR by NMR. Science 274, 1531-1534.

    Article  PubMed  ADS  CAS  Google Scholar 

  • Stockman B. and Dalvit C. 2002. NMR screening techniques in drug discovery and drug design. Prog. Nucl. Mag. Reson. Spectrosc. 41, 187-231.

    Article  CAS  Google Scholar 

  • Szczepankiewicz B. G., Liu G., Hajduk P. J., Abad-Zapatero C., Pei Z., Xin Z., Lubben T. H., Trevillyan J. M., Stashko M. A., Ballaron S. J., et al 2003. Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J. Am. Chem. Soc. 125, 4087-4096.

    Article  PubMed  CAS  Google Scholar 

  • Teague S. J., Davis A. M., Leeson P. D. and Oprea T. 1999. The design of leadlike combinatorial libraries. Angew. Chem. Int. Ed. 38, 3743-3747.

    Article  CAS  Google Scholar 

  • van, Dongen M., Uppenberg J., Svensson B., Lundbäck T., Åkerud T., Wikström M. and Schultz J. 2002a. Structure-Based Screening As Applied to Human FABP4: A Highly Efficient Alternative to HTS for Hit Generation. J. Am. Chem. Soc. 124, 11874-11880.

    Google Scholar 

  • van, Dongen M., Weigelt J., Uppenberg J., Schultz J. and Wikstrom M. 2002b. Structure-based screening and design in drug discovery. Drug Discov Today 7, 471-478.

    Google Scholar 

  • Wyss D. F., Arasappan A., Senior M. M., Wang, Y-S, Beyer B. M., Njoroge F. G. and McCoy M. A. 2004. Non-peptidic small molecule inhibitors of the single-chain hepatitic C virus NS3 protease NS4A cofactor complex discovered by structure-based NMR screening. J. Med. Chem. 47, 2486-2498.

    Article  PubMed  CAS  Google Scholar 

  • Wyss D. F., McCoy M. A. and Senior M. M. 2002. NMR-based approaches for lead discovery. Curr. Opin. Drug. Discov. Devel. 5, 630-647.

    PubMed  CAS  Google Scholar 

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Lepre, C.A., Moore, J.M. (2007). Fragment-Based NMR Screening in Lead Discovery. In: Structure-Based Drug Discovery. Springer, Dordrecht. https://doi.org/10.1007/1-4020-4407-0_4

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