Publikationsserver der Universitätsbibliothek Marburg
Titel:Strukturbasierte Entwicklung und Charakterisierung von Inhibitoren der TGT,ein mögliches Ziel zur Therapie der Bakterienruhr
Autor:Ehrmann, Frederik Rainer
Weitere Beteiligte: Klebe, Gerhard (Prof.Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0064
DOI: https://doi.org/10.17192/z2017.0064
URN: urn:nbn:de:hebis:04-z2017-00648
DDC: Allgemeines, Wissenschaft
Titel (trans.):Structure based design and characterization of TGT inhibitors, a putative target for therapy of Shigellosis
Publikationsdatum:2017-02-07
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Homodimer, Proteine, Homodimer, TGT, Bakterienruhr, Arzneimitteldesign, Drug design, Inhibitor, Shigellosis, Kristallisation, Inhibitor

Zusammenfassung:
Das Zielenzym TGT hat eine essentielle Bedeutung für die Pathogenese der entzündlichen Darmerkrankung Bakterienruhr, die durch Shigellen verursacht wird. Die TGT tauscht dazu die Purinbase Guanin in der Wobble Position-34 von verschiedenen tRNAs durch die modifizierte Base preQ1 aus. Die von den Purinbasen abgeleiteten lin-Benzoguanin Inhibitoren binden im aktiven Zentrum der Basenaustauschreaktion. Durch Anfügen von Substituenten können die benachbarten Ribose-33 und Ribose-34-Taschen adressiert werden. In zwei Studien wurden die Wassernetzwerke der genannten Seitentaschen ladungsneutral durch Monosaccharid-Substituenten der lin-Benzoguanin Inhibitoren adressiert und verdrängt. Dabei binden die Furanosyl-Substituenten räumlich gesehen in einer vergleichbaren Region wie die Phosphatgruppe-35 des natürlichen tRNA-Substrats. Dies lässt den Rückschluss zu, dass Furanoside als mögliche Surrogate für die Adressierung von Phosphatbindetaschen geeignet sind. Da die TGT nur als Homodimer das natürliche tRNA-Substrat modifiziert, kommen als Inhibitionsmechanismen sowohl die Blockierung des aktiven Zentrums, als auch die Störung der dimeren Quartärstruktur der TGT, in Frage. Die Kontaktfläche der zwei TGT Monomere liegt in unmittelbarer Nähe zu der Ribose-34-Tasche. Bei der Analyse der Kokristallstrukturen der Furanosyl-substituierten Inhibitoren fiel auf, dass durch Adressierung des hydrophoben Bereichs der Seitentasche ein angrenzendes Loop-Helix Motiv in seiner geometrischen Integrität gestört wird. Da dieses Motiv entscheidend zur Dimerstabilität beiträgt und die Umlagerungen nur in Kokristallstrukturen auftreten, wurden in einer vertieften Studie bereits charakterisierte Liganden kokristallisiert, von denen zuvor nur eine durch die Soaking-Methode erhaltene Kristallstruktur vorlag. Die Analyse dieser Kokristallstrukturen offenbarte zum einen andere Bindungsmodi als in den Soaking-Kristallstrukturen und bestätigte zum anderen weitere Liganden, die das Interface der TGT stören. Die Dimer-destabilisierende Wirkung dieser Liganden wurde durch native Massenspektroskopie bestätigt. Ein Ligand induziert durch seine Bindung eine neuartige Ausrichtung des TGT-Dimers (verdrehtes Dimer), welche offensichtlich aufgrund der verdrehten Neuausrichtung nicht mehr katalytisch aktiv sein kann. In einer Folgestudie konnten drei Inhibitoren charakterisiert werden, die ebenfalls die Dimerisierung der TGT stören. Zwei dieser Verbindungen kokristallisieren sowohl in dem konventionellen, als auch in dem verdrehten Dimer. Eine weitere Studie verfolgte den Prodrug-Ansatz. Da die lin-Benzoguanin-Inhibitoren nicht membrangängig sind, wurde das Grundgerüst mit unterschiedlichen Carbamat-Substituenten versehen. Infolge konnten PAMPA-Messungen zum ersten Mal membrangängige Liganden der TGT bestätigen. In einer Art retrospektiven Arbeit wurden die Bindungsbeiträge der Aminosäuren der Guanin 34/preQ1 Tasche auf die Affinitäten der untersuchten Liganden aufgeklärt. Anhand von Benzimidazol-Derivaten wurde eine zuvor durch eine MD-Simulation prognostizierte Taschenerweiterung erstmals in Kokristallstrukturen experimentell bestätigt. Sowohl Hydrazid-, als auch Guanidin-Substituenten des Benzimidazol-Grundkörpers, stabilisieren aufgrund ihres sterischen Drucks auf Asp156 und der Solvatisierung von Gln203 und Gly230 die transiente Taschenerweiterung. In zukünftigen Designzyklen könnten die Guanidin-Benzimidazole derivatisiert werden, um den neuen Hohlraum zu adressieren und so neue Affinitätspotentiale zu nutzen. Ein weiteres Projekt verfolgte die Charakterisierung eines Nukleosidderivats, welches als mögliches Übergangszustand-Analogon die Basenaustauschreaktion der TGT inhibiert. Der entwickelte Deazaguanin-basierte Inhibitor stellt eine neue Verbindungsklasse und mögliche Leitstruktur dar, die in Zukunft die etablierten lin-Benzoguanine ablösen könnte. In einem größer angelegten Projekt wurde von neun Kristallographen der AG Klebe die in-house Fragmentbibliothek durch Soaking-Kristallstrukturen an das Zielenzym Endothiapepsin röntgenkristallographisch durchgemustert. Von 361 Soaking Kristallstrukturen wurden 71 Komplexstrukturen (Trefferquote 20%) erhalten. Im Zuge dieses Projektes wurde auch ein standardisiertes Verfeinerungsprotokoll entwickelt, welches die Identifizierung von Fragmenten in Kristallstrukturen optimiert und automatisiert. Aufgrund der strukturellen Information der Fragmente in den Kristallstrukturen konnten zum einen neue funktionelle Gruppen zur Adressierung der katalytischen Diade, als auch drei Hotspots abseits des aktiven Zentrums, identifiziert werden. Neben der Demaskierung eines falsch-positiven Treffers aus biophysikalischen Screening-Verfahren, wurde auch offensichtlich, dass die in der Praxis häufig verwendeten biophysikalischen Methoden zum Vor-Screening von Fragmentbibliotheken die Anzahl der Treffer und somit mögliche Röntgenkomplexstrukturen nicht unbedingt erhöht sondern gegebenenfalls reduziert.

Bibliographie / References

  1. [221] Jakobi, S. (2013). Nichtkompetitive Inhibition der tRNA-Guanin Transglycosylase durch Störung der essentiellen Protein-Protein-Interaktion, http://dx.doi.org/10.17192/z2013.0380 ed. Philipps-Universität Marburg.
  2. [220] Neeb, M. (2014). Investigations on lin-Benzopurines With Respect to Dissociation Behavior, Pocket Cross-Talk, Targeting Resistance Mutants, Residual Mobility, and Scaffold Optimization, http://dx.doi.org/10.17192/z2014.0419 ed. Philipps-Universität Marburg.
  3. [184] Aramini, James M., Hamilton, K., Ma, L.-C., Swapna, G. V. T., Leonard, Paul G., Ladbury, John E., Krug, Robert M. & Montelione, Gaetano T. (2014) 19F NMR Reveals Multiple Conformations at the Dimer Interface of the Nonstructural Protein 1 Effector Domain from Influenza A Virus. Structure 22, 515-525.
  4. [196] Lewandowicz, A., Tyler, P. C., Evans, G. B., Furneaux, R. H. & Schramm, V. L. (2003) Achieving the Ultimate Physiological Goal in Transition State Analogue Inhibitors for Purine Nucleoside Phosphorylase. J. Biol. Chem. 278, 31465-31468.
  5. [163] Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M. & Leeson, P. D. (2003) A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs. J. Med. Chem. 46, 1250-1256.
  6. Egile, C., Loisel, T. P., Laurent, V., Li, R., Pantaloni, D., Sansonetti, P. J. & Carlier, M.-F. (1999) Activation of the Cdc42 Effector N-Wasp by the Shigella flexneri Icsa Protein Promotes Actin Nucleation by Arp2/3 Complex and Bacterial Actin-Based Motility. J. Biol. Chem. 146, 1319- 1332.
  7. Bissantz, C., Kuhn, B. & Stahl, M. (2010) A Medicinal Chemist's Guide to Molecular Interactions. Journal of medicinal chemistry 53, 5061-5084.
  8. [176] Liang, J., Edelsbrunner, H., Fu, P., Sudhakar, P. V. & Subramaniam, S. (1998) Analytical Shape Computation of Macromolecules: I. Molecular Area and Volume Through Alpha Shape. Proteins: Struct., Funct., Bioinf. 33, 1-17.
  9. Grädler, U., Gerber, H.-D., Goodenough-Lashua, D. M., Garcia, G. A., Ficner, R., Reuter, K., Stubbs, M. T. & Klebe, G. (2001) A New Target for Shigellosis: Rational Design and Crystallographic Studies of Inhibitors of tRNA-Guanine Transglycosylase. J. Mol. Biol. 306, 455-467.
  10. [207] Wang, S., Haapalainen, A. M., Yan, F., Du, Q., Tyler, P. C., Evans, G. B., Rinaldo-Matthis, A., Brown, R. L., Norris, G. E., Almo, S. C. & Schramm, V. L. (2012) A Picomolar Transition State Analogue Inhibitor of MTAN as a Specific Antibiotic for H. pylori. Biochemistry 51, 6892-6894.
  11. [170] Spyrakis, F., Benedetti, P., Decherchi, S., Rocchia, W., Cavalli, A., Alcaro, S., Ortuso, F., Baroni, M. & Cruciani, G. (2015) A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins. J. Chem. Inf. Model. 55, 2256- 2274.
  12. [216] Cooper, J. B. (2002) Aspartic Proteinases in Disease: A Structural Perspective. Curr. Drug Targets 3, 155-173.
  13. Tran Van Nhieu, G., Bourdet-Sicard, R., Duménil, G., Blocker, A. & Sansonetti, P. J. (2000) Bacterial Signals and Cell Responses During Shigella Entry into Epithelial Cells. Cell. Microbiol.
  14. [119] Neeb, M., Betz, M., Heine, A., Barandun, L. J., Hohn, C., Diederich, F. & Klebe, G. (2014) Beyond Affinity: Enthalpy-Entropy Factorization Unravels Complexity of a Flat StructureActivity Relationship for Inhibition of a tRNA-Modifying Enzyme. J. Med. Chem. 57, 5566- 5578.
  15. Phillips, G., El Yacoubi, B., Lyons, B., Alvarez, S., Iwata-Reuyl, D. & de Crecy-Lagard, V. (2008) Biosynthesis of 7-Deazaguanosine-modified tRNA Nucleosides: A New Role for GTP Cyclohydrolase I. J. Bacteriol. 190, 7876-7884.
  16. [112] McCarty, R. M. & Bandarian, V. (2012) Biosynthesis of Pyrrolopyrimidines. Bioorg. Chem. 43, 15-25.
  17. Iwata-Reuyl, D. (2003) Biosynthesis of the 7-Deazaguanosine Hypermodified Nucleosides of transfer RNA. Bioorg. Chem. 31, 24-43.
  18. [128] Mannhold, R., Poda, G. I., Ostermann, C. & Tetko, I. V. (2009) Calculation of Molecular Lipophilicity: State-of-the-Art and Comparison of Log P Methods on more than 96,000 Compounds. J. Pharm. Sci. 98, 861-893.
  19. [161] Walko, C. M. & Lindley, C. (2005) Capecitabine: A Review. Clin. Ther. 27, 23-44.
  20. [152] Philip, M. P. & Randy, M. W. (2006) Carboxylesterases - Detoxifying Enzymes and Targets for Drug Therapy. Curr. Med. Chem. 13, 1045-1054.
  21. [177] Dundas, J., Ouyang, Z., Tseng, J., Binkowski, A., Turpaz, Y. & Liang, J. (2006) CASTp: Computed Atlas of Surface Topography of Proteins with Structural and Topographical Mapping of Functionally Annotated Residues. Nucleic Acids Res. 34, W116-W118.
  22. [118] Neeb, M., Czodrowski, P., Heine, A., Barandun, L. J., Hohn, C., Diederich, F. & Klebe, G. (2014) Chasing Protons: How Isothermal Titration Calorimetry, Mutagenesis, and pKa Calculations Trace the Locus of Charge in Ligand Binding to a tRNA-Binding Enzyme. J. Med. Chem. 57, 5554-5565.
  23. [146] Albert, A. (1958) Chemical Aspects of Selective Toxicity. Nature 182, 421-423.
  24. Barillari, C., Taylor, J., Viner, R. & Essex, J. W. (2007) Classification of Water Molecules in Protein Binding Sites. J. Am. Chem. Soc. 129, 2577-2587.
  25. [185] Levine, M. M., Kotloff, K. L., Barry, E. M., Pasetti, M. F. & Sztein, M. B. (2007) Clinical Trials of Shigella Vaccines: Two Steps Forward and One Step Back on a Long, Hard Road. Nat. Rev. Microbiol. 5, 540-553.
  26. Lin, J., Lee, I. S., Frey, J., Slonczewski, J. L. & Foster, J. W. (1995) Comparative Analysis of Extreme Acid Survival in Salmonella typhimurium, Shigella flexneri, and Escherichia coli. J.
  27. [186] Gu, B., Cao, Y., Pan, S., Zhuang, L., Yu, R., Peng, Z., Qian, H., Wei, Y., Zhao, L., Liu, G. & Tong, M. (2012) Comparison of the Prevalence and Changing Resistance to Nalidixic Acid and Ciprofloxacin of Shigella between Europe-America and Asia-Africa from 1998 to 2009. Int. J. Antimicrob. Agents 40, 9-17.
  28. [166] Grünberg, R., Leckner, J. & Nilges, M. (2004) Complementarity of Structure Ensembles in Protein-Protein Binding. Structure 12, 2125-2136.
  29. [130] Taha, H. A., Richards, M. R. & Lowary, T. L. (2013) Conformational Analysis of FuranosideContaining Mono- and Oligosaccharides. Chem. Rev. 113, 1851-1876.
  30. [115] Ritschel, T., Hörtner, S., Heine, A., Diederich, F. & Klebe, G. (2009) Crystal Structure Analysis and in silico pKa Calculations Suggest Strong pKa Shifts of Ligands as Driving Force for HighAffinity Binding to TGT. Chembiochem. 10, 716-727.
  31. Romier, C., Reuter, K., Suck, D. & Ficner, R. (1996) Crystal Structure of tRNA-Guanine Transglycosylase: RNA Modification by Base Exchange. EMBO J. 15, 2850-2857.
  32. [137] Stengl, B., Meyer, E. A., Heine, A., Brenk, R., Diederich, F. & Klebe, G. (2007) Crystal structures of tRNA-Guanine Transglycosylase (TGT) in Complex with Novel and Potent Inhibitors Unravel Pronounced Induced-Fit Adaptations and Suggest Dimer Formation Upon Substrate Binding. J. Mol. Biol. 370, 492-511.
  33. [158] Siddiqui, F. M. & Qureshi, A. I. (2010) Dabigatran Etexilate, a New Oral Direct Thrombin Inhibitor, for Stroke Prevention in Patients with Atrial Fibrillation. Expert Opin. Pharmacother. 11, 1403-1411.
  34. [157] van Ryn, J., Stangier, J., Haertter, S., Liesenfeld, K. H., Wienen, W., Feuring, M. & Clemens, A. (2010) Dabigatran Etexilate - a Novel, Reversible, Oral Direct Thrombin Inhibitor: Interpretation of Coagulation Assays and Reversal of Anticoagulant Activity. Thromb. Haemostasis 103, 1116-1127.
  35. [162] Waring, M. J. (2009) Defining Optimum Lipophilicity and Molecular Weight Ranges for Drug Candidates-Molecular Weight Dependent Lower logD Limits Based on Permeability. Bioorg. Med. Chem. Lett. 19, 2844-2851.
  36. [159] Miwa, M., Ura, M., Nishida, M., Sawada, N., Ishikawa, T., Mori, K., Shimma, N., Umeda, I. & Ishitsuka, H. (1998) Design of a Novel Oral Fluoropyrimidine Carbamate, Capecitabine, which Generates 5-Fluorouracil Selectively in Tumours by Enzymes Concentrated in Human Liver and Cancer Tissue. Eur. J. Cancer 34, 1274-1281.
  37. [151] Beaumont, K., Webster, R., Gardner, I. & Dack, K. (2003) Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist. Curr. Drug Metab. 4, 461-485.
  38. [208] Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. (1996) Discovering High-Affinity Ligands for Proteins: SAR by NMR. Science 274, 1531-1534.
  39. [171] Schames, J. R., Henchman, R. H., Siegel, J. S., Sotriffer, C. A., Ni, H. & McCammon, J. A. (2004) Discovery of a Novel Binding Trench in HIV Integrase. J. Med. Chem. 47, 1879-1881.
  40. [217] Geschwindner, S., Olsson, L.-L., Albert, J. S., Deinum, J., Edwards, P. D., de Beer, T. & Folmer, R. H. A. (2007) Discovery of a Novel Warhead against β-Secretase through Fragment-Based Lead Generation. J. Med. Chem. 50, 5903-5911.
  41. [129] van de Waterbeemd, H., Lennernas, H., Artursson, L., Mannhold, R., Kubinyi, H. & Folkers, G. (2006). Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.
  42. McCarty, R. M., Somogyi, Á. & Bandarian, V. (2009) E. coli QueD is a 6-Carboxy-5,6,7,8- tetrahydropterin Synthase. Biochemistry 48, 2301-2303.
  43. Michel, J., Tirado-Rives, J. & Jorgensen, W. L. (2009) Energetics of Displacing Water Molecules from Protein Binding Sites: Consequences for Ligand Optimization. J. Am. Chem.
  44. [225] Fukada, H. & Takahashi, K. (1998) Enthalpy and Heat Capacity Changes for the Proton Dissociation of Various Buffer Components in 0.1 M Potassium Chloride. Proteins: Struct. Funct. Genet. 33, 159-166.
  45. [145] Fenley, A. T., Muddana, H. S. & Gilson, M. K. (2012) Entropy-Enthalpy Transduction Caused by Conformational Shifts can Obscure the Forces Driving Protein-Ligand Binding. Proc. Natl. Acad. Sci. U. S. A. 109, 20006-20011.
  46. [203] Schramm, V. L. (2011) Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes. Annu. Rev. Biochem. 80, 703-732.
  47. [155] Kumpulainen, H., Mähönen, N., Laitinen, M.-L., Jaurakkajärvi, M., Raunio, H., Juvonen, R. O., Vepsäläinen, J., Järvinen, T. & Rautio, J. (2006) Evaluation of Hydroxyimine as Cytochrome P450-Selective Prodrug Structure. J. Med. Chem. 49, 1207-1211.
  48. Chen, Y. C., Brooks, A. F., Goodenough-Lashua, D. M., Kittendorf, J. D., Showalter, H. D. & Garcia, G. A. (2011) Evolution of Eukaryal tRNA-Guanine Transglycosylase: Insight Gained from the Heterocyclic Substrate Recognition by the Wild-Type and Mutant Human and Escherichia coli tRNA-Guanine Transglycosylases. Nucleic Acids Res. 39, 2834-2844.
  49. [189] Evans, G. B., Furneaux, R. H., Lewandowicz, A., Schramm, V. L. & Tyler, P. C. (2003) Exploring Structure−Ac vity Rela onships of Transi on State Analogues of Human Purine Nucleoside Phosphorylase. J. Med. Chem. 46, 3412-3423.
  50. [172] Zürcher, M., Gottschalk, T., Meyer, S., Bur, D. & Diederich, F. (2008) Exploring the Flap Pocket of the Antimalarial Target Plasmepsin II: The “55 % Rule” Applied to Enzymes. ChemMedChem 3, 237-240.
  51. [168] Gerstein, M. & Echols, N. (2004) Exploring the Range of Protein Flexibility, From a Structural Proteomics Perspective. Curr. Opin. Chem. Biol. 8, 14-19.
  52. [147] Hann, M. M. & Keserü, G. M. (2012) Finding the Sweet Spot: The Role of Nature and Nurture in Medicinal Chemistry. Nat. Rev. Drug Discovery 11, 355-365.
  53. Brenk, R., Stubbs, M. T., Heine, A., Reuter, K. & Klebe, G. (2003) Flexible Adaptations in the Structure of the tRNA-modifying enzyme tRNA-guanine Transglycosylase and their Implications for Substrate Selectivity, Reaction Mechanism and Structure-Based Drug Design.
  54. [209] Scott, D. E., Coyne, A. G., Hudson, S. A. & Abell, C. (2012) Fragment-Based Approaches in Drug Discovery and Chemical Biology. Biochemistry 51, 4990-5003.
  55. [211] Erlanson, D. A., McDowell, R. S. & O'Brien, T. (2004) Fragment-Based Drug Discovery. J. Med. Chem. 47, 3463-3482.
  56. [210] Rees, D. C., Congreve, M., Murray, C. W. & Carr, R. (2004) Fragment-Based Lead Discovery. Nat. Rev. Drug Discovery 3, 660-672.
  57. [215] Joseph-McCarthy, D., Campbell, A. J., Kern, G. & Moustakas, D. (2014) Fragment-Based Lead Discovery and Design. J. Chem. Inf. Model. 54, 693-704.
  58. [214] Baker, M. (2013) Fragment-Based Lead Discovery Grows up. Nat. Rev. Drug Discovery 12, 5-7.
  59. [120] Riniker, S., Barandun, L. J., Diederich, F., Kramer, O., Steffen, A. & van Gunsteren, W. F. (2012) Free Enthalpies of Replacing Water Molecules in Protein Binding Pockets. J. Comput.- Aided Mol. Des. 26, 1293-1309.
  60. [114] Barandun, L. J., Immekus, F., Kohler, P. C., Tonazzi, S., Wagner, B., Wendelspiess, S., Ritschel, T., Heine, A., Kansy, M., Klebe, G. & Diederich, F. (2012) From lin-Benzoguanines to linBenzohypoxanthines as Ligands for Zymomonas mobilis tRNA-Guanine Transglycosylase: Replacement of Protein-Ligand Hydrogen Bonding by Importing Water Clusters. Chem. Eur. J. 18, 9246-9257.
  61. Suzuki, T., Saga, S. & Sasakawa, C. (1996) Functional Analysis of Shigella VirG Domains Essential for Interaction with Vinculin and Actin-based Motility. J. Biol. Chem. 271, 21878- 21885.
  62. [202] Tidten, N., Stengl, B., Heine, A., Garcia, G. A., Klebe, G. & Reuter, K. (2007) Glutamate Versus Glutamine Exchange Swaps Substrate Selectivity in tRNA-Guanine Transglycosylase: Insight Into the Regulation of Substrate Selectivity by Kinetic and Crystallographic Studies. J. Mol. Biol. 374, 764-776.
  63. [224] Leatherbarrow, R. J. (1992). GraFit Version 4.09, Erithacus Software Ltd., Staines, U.K.
  64. Gajiwala, K. S. & Burley, S. K. (2000) HDEA, a Periplasmic Protein that Supports Acid Resistance in Pathogenic Enteric Bacteria1. J. Mol. Biol. 295, 605-612.
  65. [116] Barandun, L. J., Immekus, F., Kohler, P. C., Ritschel, T., Heine, A., Orlando, P., Klebe, G. & Diederich, F. (2013) High-Affinity Inhibitors of Zymomonas mobilis tRNA-Guanine Transglycosylase through Convergent Optimization. Acta Crystallogr., Sect. D 69, 1798-1807.
  66. Beuming, T., Farid, R. & Sherman, W. (2009) High-Energy Water Sites Determine Peptide Binding Affinity and Specificity of PDZ Domains. Protein Sci. 18, 1609-1619.
  67. [227] Keller, S., Vargas, C., Zhao, H., Piszczek, G., Brautigam, C. A. & Schuck, P. (2012) HighPrecision Isothermal Titration Calorimetry with Automated Peak-Shape Analysis. Anal. Chem. 84, 5066-5073.
  68. Reader, J. S., Metzgar, D., Schimmel, P. & de Crécy-Lagard, V. (2004) Identification of Four Genes Necessary for Biosynthesis of the Modified Nucleoside Queuosine. J. Biol. Chem. 279, 6280-6285.
  69. [187] Sawhney, B., Chopra, K., Misra, R. & Ranjan, A. (2015) Identification of Plasmodium falciparum Apicoplast-Targeted tRNA-Guanine Transglycosylase and its Potential Inhibitors Using Comparative Genomics, Molecular Modelling, Docking and Simulation Studies. J. Biomol. Struct. Dyn. 33, 2404-2420.
  70. [117] Grüner, S., Neeb, M., Barandun, L. J., Sielaff, F., Hohn, C., Kojima, S., Steinmetzer, T., Diederich, F. & Klebe, G. (2014) Impact of Protein and Ligand Impurities on ITC-Derived Protein-Ligand Thermodynamics. Biochim. Biophys. Acta 1840, 2843-2850.
  71. [198] Schrödinger Release 2014-2013: Impact Version 6.4 (2014). New York, NY: Schrödinger.
  72. [173] Durrant, J. D., de Oliveira, C. A. F. & McCammon, J. A. (2010) Including Receptor Flexibility and Induced Fit Effects into the Design of MMP-2 Inhibitors. J. Mol. Recognit. 23, 173-182.
  73. [167] Meagher, K. L. & Carlson, H. A. (2004) Incorporating Protein Flexibility in Structure-Based Drug Discovery:  Using HIV-1 Protease as a Test Case. J. Am. Chem. Soc. 126, 13276-13281.
  74. [138] Krissinel, E. & Henrick, K. (2007) Inference of Macromolecular Assemblies From Crystalline State. J. Mol. Biol. 372, 774-797.
  75. [206] Roday, S., Amukele, T., Evans, G. B., Tyler, P. C., Furneaux, R. H. & Schramm, V. L. (2004) Inhibition of Ricin A-Chain with Pyrrolidine Mimics of the Oxacarbenium Ion Transition State. Biochemistry 43, 4923-4933.
  76. [201] Meyer, E. A., Castellano, R. K. & Diederich, F. (2003) Interactions with Aromatic Rings in Chemical and Biological Recognition. Angew. Chem., Int. Ed. 42, 1210-1250.
  77. Hoagland, M. B., Zamecnik, P. C. & Stephenson, M. L. (1957) Intermediate Reactions in Protein Biosynthesis. Biochim. Biophys. Acta 24, 215-216.
  78. [153] Yang, C. Y., Dantzig, A. H. & Pidgeon, C. (1999) Intestinal Peptide Transport Systems and Oral Drug Availability. Pharm. Res. 16, 1331-1343.
  79. Biela, I., Tidten-Luksch, N., Immekus, F., Glinca, S., Nguyen, T. X., Gerber, H. D., Heine, A., Klebe, G. & Reuter, K. (2013) Investigation of Specificity Determinants in Bacterial tRNAGuanine Transglycosylase Reveals Queuine, the Substrate of its Eucaryotic Counterpart, as Inhibitor. PloS one 8, e64240.
  80. [122] Clarke, C., Woods, R. J., Gluska, J., Cooper, A., Nutley, M. A. & Boons, G.-J. (2001) Involvement of Water in Carbohydrate−Protein Binding. J. Am. Chem. Soc. 123, 12238-12247.
  81. [199] Sauve, A. A., Cahill, S. M., Zech, S. G., Basso, L. A., Lewandowicz, A., Santos, D. S., Grubmeyer, C., Evans, G. B., Furneaux, R. H., Tyler, P. C., McDermott, A., Girvin, M. E. & Schramm, V. L. (2003) Ionic States of Substrates and Transition State Analogues at the Catalytic Sites of NRibosyltransferases†. Biochemistry 42, 5694-5705.
  82. Okada, N. & Nishimura, S. (1979) Isolation and Characterization of a Guanine Insertion Enzyme, a Specific tRNA Transglycosylase, from Escherichia coli. J. Biol. Chem. 254, 3061- 3066.
  83. [144] Jelesarov, I. & Bosshard, H. R. (1999) Isothermal Titration Calorimetry and Differential Scanning Calorimetry as Complementary Tools to Investigate the Energetics of Biomolecular Recognition. J. Mol. Recognit. 12, 3-18.
  84. Ladbury, J. E. (1996) Just Add Water! The Effect of Water on the Specificity of Protein-Ligand Binding Sites and its Potential Application to Drug Design. Chemistry & biology 3, 973-980.
  85. [150] Ettmayer, P., Amidon, G. L., Clement, B. & Testa, B. (2004) Lessons Learned from Marketed and Investigational Prodrugs. J. Med. Chem. 47, 2393-2404.
  86. Wang, L., Berne, B. J. & Friesner, R. A. (2011) Ligand Binding to Protein-Binding Pockets with Wet and Dry Regions. Proc. Natl. Acad. Sci. U. S. A. 108, 1326-1330.
  87. Roberts, B. C. & Mancera, R. L. (2008) Ligand−Protein Docking with Water Molecules. J.
  88. [181] Gerber, P. R. & Müller, K. (1995) MAB, a Generally Applicable Molecular Force Field for Structure Modelling in Medicinal Chemistry. J. Comput.-Aided Mol. Des. 9, 251-268.
  89. [197] Schrödinger Release 2014-2013: Macro Model Version 10.5 (2014). New York; NY: Schrödinger.
  90. Lee, B. W. K., Van Lanen, S. G. & Iwata-Reuyl, D. (2007) Mechanistic Studies of Bacillus subtilis QueF, the Nitrile Oxidoreductase Involved in Queuosine Biosynthesis. Biochemistry 46, 12844-12854.
  91. [212] Hubbard, R. E. & Murray, J. B. (2011). Methods Enzymol., edited by C. K. Lawrence, pp. 509- 531: Academic Press.
  92. Krimmer, S. G., Betz, M., Heine, A. & Klebe, G. (2014) Methyl, Ethyl, Propyl, Butyl: Futile but not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors. ChemMedChem 9, 833-846.
  93. [154] Jousserandot, A., Boucher, J.-L., Henry, Y., Niklaus, B., Clement, B. & Mansuy, D. (1998) Microsomal Cytochrome P450 Dependent Oxidation of N-Hydroxyguanidines, Amidoximes, and Ketoximes:  Mechanism of the Oxidative Cleavage of Their CN(OH) Bond with Formation of Nitrogen Oxides. Biochemistry 37, 17179-17191.
  94. Minimal tRNA Structure and Sequence Requirements for Recognition. J. Biol. Chem. 270, 17264-17267.
  95. Verdonk, M. L., Chessari, G., Cole, J. C., Hartshorn, M. J., Murray, C. W., Nissink, J. W. M., Taylor, R. D. & Taylor, R. (2005) Modeling Water Molecules in Protein−Ligand Docking Using GOLD. J. Med. Chem. 48, 6504-6515.
  96. [136] Yang, C., Li, P., Zhang, X., Ma, Q., Cui, X., Li, H., Liu, H., Wang, J., Xie, J., Wu, F., Sheng, C., Du, X., Qi, L., Su, W., Jia, L., Xu, X., Zhao, J., Xia, S., Zhou, N., Ma, H., Qiu, S. & Song, H. (2016) Molecular Characterization and Analysis of High-Level Multidrug-Resistance of Shigella flexneri Serotype 4s Strains from China. Sci Rep. 6, 29124.
  97. [169] Karplus, M. & McCammon, J. A. (2002) Molecular dynamics simulations of biomolecules. Nat. Struct. Mol. Biol. 9, 646-652.
  98. Schröder, G. N. & Hilbi, H. (2008) Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion. Clin. Microbiol. Rev. 21, 134-156.
  99. Ellermann, M., Jakob-Roetne, R., Lerner, C., Borroni, E., Schlatter, D., Roth, D., Ehler, A., Rudolph, M. G. & Diederich, F. (2009) Molecular Recognition at the Active Site of Catechol-oMethyltransferase: Energetically Favorable Replacement of a Water Molecule Imported by a Bisubstrate Inhibitor. Angew. Chem., Int. Ed. 48, 9092-9096.
  100. Frey, B., McCloskey, J., Kersten, W. & Kersten, H. (1988) New Function of Vitamin B12: Cobamide-Dependent Reduction of Epoxyqueuosine to Queuosine in tRNAs of Escherichia coli and Salmonella typhimurium. J. Bacteriol. 170, 2078-2082.
  101. [182] Bruno, I. J., Cole, J. C., Edgington, P. R., Kessler, M., Macrae, C. F., McCabe, P., Pearson, J. & Taylor, R. (2002) New Software for Searching the Cambridge Structural Database and Visualizing Crystal Structures. Acta Crystallogr., Sect. B 58, 389-397.
  102. [135] Okada, N., Noguchi, S., Kasai, H., Shindo-Okada, N., Ohgi, T., Goto, T. & Nishimura, S. (1979) Novel Mechanism of Post-Transcriptional Modification of tRNA. Insertion of Bases of Q Precursors into tRNA by a Specific tRNA Transglycosylase Reaction. J. Biol. Chem. 254, 3067-3073.
  103. Suzuki, T. & Sasakawa, C. (1998) N-WASP is an Important Protein for the Actin-Based Motility of Shigella flexneri in the Infected Epithelial Cells. Jpn. J. Med. Sci. Biol. 51, S63-S68.
  104. [219] Schechter, I. & Berger, A. (1967) On the Size of the Active Site in Proteases. I. Papain. Biochem. Biophys. Res. Commun. 27, 157-162.
  105. [132] Rye, C. S. & Baell, J. B. (2005) Phosphate Isosteres in Medicinal Chemistry. Curr. Med. Chem. 12, 3127-3141.
  106. Hirsch, A. K. H., Fischer, F. R. & Diederich, F. (2007) Phosphate Recognition in Structural Biology. Angew. Chem., Int. Ed. 46, 338-352.
  107. [164] Kansy, M., Senner, F. & Gubernator, K. (1998) Physicochemical High Throughput Screening:  Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes. J. Med. Chem. 41, 1007-1010.
  108. [204] Barbieri, L., Valbonesi, P., Gorini, P., Pession, A. & Stirpe, F. (1996) Polynucleotide: Adenosine Glycosidase Activity of Saporin-L1: Effect on DNA, RNA and poly(A). Biochem. J. 319, 507-513.
  109. [191] Balakrishnan, K., Ravandi, F., Bantia, S., Franklin, A. & Gandhi, V. (2013) Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia. Clin. Lymphoma, Myeloma Leuk. 13, 458-466.
  110. [148] Huttunen, K. M. & Rautio, J. (2011) Prodrugs - An Efficient Way to Breach Delivery and Targeting Barriers. Curr. Top. Med. Chem. 11, 2265-2287.
  111. [149] Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Jarvinen, T. & Savolainen, J. (2008) Prodrugs: Design and Clinical Applications. Nat. Rev. Drug Discovery 7, 255-270.
  112. [160] Sinhababu, A. K. & Thakker, D. R. (1996) Prodrugs of Anticancer Agents. Adv. Drug Delivery Rev. 19, 241-273.
  113. Hunter, T. (1995) Protein Kinases and Phosphatases: The Yin and Yang of Protein Phosphorylation and Signaling. Cell 80, 225-236.
  114. Romier, C., Ficner, R., Reuter, K. & Suck, D. (1996) Purification, Crystallization, and Preliminary X-Ray Diffraction Studies of tRNA-Guanine Transglycosylase from Zymomonas mobilis. Proteins: Struct., Funct., Bioinf. 24, 516-519.
  115. [190] Robak, T., Lech-Maranda, E., Korycka, A. & Robak, E. (2006) Purine Nucleoside Analogs as Immunosuppressive and Antineoplastic Agents: Mechanism of Action and Clinical Activity. Curr. Med. Chem. 13, 3165-3189.
  116. [193] Erion, M. D., Stoeckler, J. D., Guida, W. C. & Walter, R. L. (1997) Purine Nucleoside Phosphorylase. 2. Catalytic Mechanism. Biochemistry 36, 11735-11748.
  117. [195] Basso, L. A., Santos, D. S., Shi, W., Furneaux, R. H., Tyler, P. C., Schramm, V. L. & Blanchard, J. S. (2001) Purine Nucleoside Phosphorylase from Mycobacterium Tuberculosis. Analysis of Inhibition by a Transition-State Analogue and Dissection by Parts. Biochemistry 40, 8196- 8203.
  118. [123] Tschampel, S. M. & Woods, R. J. (2003) Quantifying the Role of Water in Protein−Carbohydrate Interac ons. J. Phys. Chem. A 107, 9175-9181.
  119. [178] Morris, R. C. & Elliott, M. S. (2001) Queuosine modification of tRNA: A Case for Convergent Evolution. Mol. Genet. Metab. 74, 147-159.
  120. [174] Hicks, C. & Gulick, R. M. (2009) Raltegravir: The First HIV Type 1 Integrase Inhibitor. Clin. Infect. Dis. 48, 931-939.
  121. [141] Wiseman, T., Williston, S., Brandts, J. F. & Lin, L.-N. (1989) Rapid Measurement of Binding Constants and Heats of Binding Using a New Titration Calorimeter. Anal. Biochem. 179, 131- 137.
  122. Amadasi, A., Surface, J. A., Spyrakis, F., Cozzini, P., Mozzarelli, A. & Kellogg, G. E. (2008) Robust Classification of “Relevant” Water Molecules in Putative Protein Binding Sites. J. Med.
  123. [142] Ladbury, J. E. & Chowdhry, B. Z. (1996) Sensing the Heat: The Application of Isothermal Titration Calorimetry to Thermodynamic Studies of Biomolecular Interactions. Chem. Biol. 3, 791-801.
  124. Reuter, K. & Ficner, R. (1995) Sequence Analysis and Overexpression of the Zymomonas mobilis tgt Gene Encoding tRNA-Guanine Transglycosylase: Purification and Biochemical Characterization of the Enzyme. J. Bacteriol. 177, 5284-5288.
  125. Marteyn, B., Gazi, A. & Sansonetti, P. (2012) Shigella: A Model of Virulence Regulation in vivo.
  126. Jennison, A. V. & Verma, N. K. (2004) Shigella flexneri Infection: Pathogenesis and Vaccine Development. FEMS Microbiol. Rev. 28, 43-58.
  127. Fernandez, M. I. & Sansonetti, P. J. (2003) Shigella Interaction with Intestinal Epithelial Cells Determines the Innate Immune Response in Shigellosis. Int. J. Med. Microbiol. 293, 55-67.
  128. [111] Sansonetti, P. J. (2006) Shigellosis: An Old Disease in New Clothes? PLoS medicine 3, e354.
  129. [180] Romier, C., Meyer, J. E. W. & Suck, D. (1997) Slight Sequence Variations of a Common Fold Explain the Substrate Specificities of tRNA-Guanine Transglycosylases from the Three Kingdoms. FEBS Lett. 416, 93-98.
  130. [140] Sheriff, S. (1993) Some Methods for Examining the Interactions Between Two Molecules. ImmunoMethods 3, 191-196.
  131. [175] Tidten, N. (2008). Structural and Mutational Characterisation of Shigella Pathogenicity Factors. Philipps-Universität Marburg.
  132. [213] Murray, C. W. & Blundell, T. L. (2010) Structural Biology in Fragment-Based Drug Design. Curr. Opin. Struct. Biol. 20, 497-507.
  133. [139] Sheriff, S., Hendrickson, W. A. & Smith, J. L. (1987) Structure of Myohemerythrin in the Azidomet State at 1.7/1.3 Å Resolution. J. Mol. Biol. 197, 273-296.
  134. Quiocho, F. A., Wilson, D. K. & Vyas, N. K. (1989) Substrate Specificity and Affinity of a Protein Modulated by Bound Water Molecules. Nature 340, 404-407.
  135. [133] Meanwell, N. A. (2011) Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 54, 2529-2591.
  136. [113] Meyer, E. A., Donati, N., Guillot, M., Schweizer, W. B., Diederich, F., Stengl, B., Brenk, R., Reuter, K. & Klebe, G. (2006) Synthesis, Biological Evaluation, and Crystallographic Studies of Extended Guanine-Based (lin-Benzoguanine) Inhibitors for tRNA-Guanine Transglycosylase (TGT). Helv. Chim. Acta 89, 573-597.
  137. [126] Saraboji, K., Håkansson, M., Genheden, S., Diehl, C., Qvist, J., Weininger, U., Nilsson, U. J., Leffler, H., Ryde, U., Akke, M. & Logan, D. T. (2012) The Carbohydrate-Binding Site in Galectin-3 Is Preorganized To Recognize a Sugarlike Framework of Oxygens: Ultra-HighResolution Structures and Water Dynamics. Biochemistry 51, 296-306.
  138. McCarty, R. M., Somogyi, Á., Lin, G., Jacobsen, N. E. & Bandarian, V. (2009) The Deazapurine Biosynthetic Pathway Revealed: In vItro Enzymatic Synthesis of preQ(0) from Guanosine-5ʹ- triphosphate in Four Steps. Biochemistry 48, 3847-3852.
  139. [223] Dixon, M. (1953) The Determination of Enzyme Inhibitor Constants. Biochem. J. 55, 170-171.
  140. [125] Li, Z. & Lazaridis, T. (2005) The Effect of Water Displacement on Binding Thermodynamics:  Concanavalin A. J. Phys. Chem. B 109, 662-670.
  141. Dunitz, J. D. (1994) The Entropic Cost of Bound Water in Crystals and Biomolecules. Science 264, 670-670.
  142. [156] Blech, S., Ebner, T., Ludwig-Schwellinger, E., Stangier, J. & Roth, W. (2008) The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans. Drug Metab. Dispos. 36, 386-399.
  143. Durand, J. M. B., Björk, G. R., Kuwae, A., Yoshikawa, M. & Sasakawa, C. (1997) The Modified Nucleoside 2-Methylthio-N6-isopentenyladenosine in tRNA of Shigella flexneri is Required for Expression of Virulence Genes. J. Bacteriol. 179, 5777-5782.
  144. [222] Gasteiger, E., Hoogland, C., Gattiker, A., Duvaud, S. e., Wilkins, M. R., Appel, R. D. & Bairoch, A. (2005). The Proteomics Protocols Handbook, edited by J. M. Walker, pp. 571-607. Totowa, NJ: Humana Press.
  145. [226] Goldberg, R. N., Kishore, N. & Lennen, R. M. (2002) Thermodynamic Quantities for the Ionization Reactions of Buffers. J. Phys. Chem. Ref. Data 31, 231-370.
  146. [124] Daranas, A. H., Shimizu, H. & Homans, S. W. (2004) Thermodynamics of Binding of d-Galactose and Deoxy Derivatives thereof to the l-Arabinose-Binding Protein. J. Am. Chem. Soc. 126, 11870-11876.
  147. Crain, P. F. & McCloskey, J. A. (1997) The RNA modification Database. Nucleic Acids Res. 25, 126-127.
  148. de Beer, S. B. A., Vermeulen, N., P. E. & Oostenbrink, C. (2010) The Role of Water Molecules in Computational Drug Design. Curr. Top. Med. Chem. 10, 55-66.
  149. [121] Minke, W. E., Diller, D. J., Hol, W. G. J. & Verlinde, C. L. M. J. (1999) The Role of Waters in Docking Strategies with Incremental Flexibility for Carbohydrate Derivatives:  Heat-Labile Enterotoxin, a Multivalent Test Case. J. Med. Chem. 42, 1778-1788.
  150. Dorman, C. J. & Porter, M. E. (1998) The Shigella Virulence Gene Regulatory Cascade: A Paradigm of Bacterial Gene Control Mechanisms. Mol. Microbiol. 29, 677-684.
  151. Levene, P. A. (1919) The Structure of Yeast Nucleic Acid: IV. Ammonia Hydrolysis. J. Biol.
  152. Wierenga, R. K. (2001) The TIM-Barrel Fold: A Versatile Framework for Efficient Enzymes.
  153. [134] Elliott, T. S., Slowey, A., Ye, Y. & Conway, S. J. (2012) The Use of Phosphate Bioisosteres in Medicinal Chemistry and Chemical Biology. MedChemComm 3, 735.
  154. [127] ACD/Labs, Version 12.01 (2009). Toronto, Canada: Advanced Chemistry Development, Inc.
  155. [179] Shindo-Okada, N., Okada, N., Ohgi, T., Goto, T. & Nishimura, S. (1980) Transfer Ribonucleic Acid Guanine Transglycosylase Isolated From Rat Liver. Biochemistry 19, 395-400.
  156. Durand, J. M. B., Dagberg, B., Uhlin, B. E. & Björk, G. R. (2000) Transfer RNA Modification, Temperature and DNA Superhelicity have a Common Target in the Regulatory Network of the Virulence of Shigella flexneri: The Expression of the virF Gene. Mol. Microbiol. 35, 924-935.
  157. [188] Garcia, G. A. & Kittendorf, J. D. (2005) Transglycosylation: A Mechanism for RNA Modification (and Editing?). Bioorg Chem 33, 229-251.
  158. [205] Sturm, M. B., Tyler, P. C., Evans, G. B. & Schramm, V. L. (2009) Transition State Analogues Rescue Ribosomes From Saporin-L1 Ribosome Inactivating Protein. Biochemistry 48, 9941- 9948.
  159. [192] Schramm, V. L. (2013) Transition States, Analogues, and Drug Development. ACS Chem. Biol. 8, 71-81.
  160. [194] Fedorov, A., Shi, W., Kicska, G., Fedorov, E., Tyler, P. C., Furneaux, R. H., Hanson, J. C., Gainsford, G. J., Larese, J. Z., Schramm, V. L. & Almo, S. C. (2001) Transition State Structure of Purine Nucleoside Phosphorylase and Principles of Atomic Motion in Enzymatic Catalysis†,‡. Biochemistry 40, 853-860.
  161. [131] Goodenough-Lashua, D. M. & Garcia, G. A. (2003) tRNA-Guanine Transglycosylase from E. coli: A Ping-Pong Kinetic Mechanism is Consistent with Nucleophilic Catalysis. Bioorg. Chem. 31, 331-344.
  162. Curnow, A. W. & Garcia, G. A. (1995) tRNA-Guanine Transglycosylase from Escherichia coli.
  163. Hoops, G. C., Townsend, L. B. & Garcia, G. A. (1995) tRNA-Guanine Transglycosylase from Escherichia coli: Structure-Activity Studies Investigating the Role of the Aminomethyl Substituent of the Heterocyclic Substrate PreQ1. Biochemistry 34, 15381-15387.
  164. Van Lanen, S. G., Kinzie, S. D., Matthieu, S., Link, T., Culp, J. & Iwata-Reuyl, D. (2003) tRNA Modification by S-Adenosylmethionine:tRNA Ribosyltransferase-Isomerase. Assay Development and Characterization of the Recombinant Enzyme. J. Biol. Chem. 278, 10491- 10499.
  165. Robinson, D. D., Sherman, W. & Farid, R. (2010) Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters. ChemMedChem 5, 618-627.
  166. Durand, J. M. B., Okada, N., Tobe, T., Watarai, M., Fukuda, I., Suzuki, T., Nakata, N., Komatsu, K., Yoshikawa, M. & Sasakawa, C. (1994) vacC, a Virulence-Associated Chromosomal Locus of Shigella flexneri, is Homologous to tgt, a Gene Encoding tRNA-Guanine Transglycosylase (Tgt) of Escherichia coli K-12. J. Bacteriol. 176, 4627-4634.
  167. Laine, R. O., Zeile, W., Kang, F., Purich, D. L. & Southwick, F. S. (1997) Vinculin Proteolysis Unmasks an ActA Homolog for Actin-based Shigella Motility. J. Cell Biol. 138, 1255-1264.
  168. [200] Brenk, R., Naerum, L., Gradler, U., Gerber, H. D., Garcia, G. A., Reuter, K., Stubbs, M. T. & Klebe, G. (2003) Virtual Screening for Submicromolar Leads of tRNA-Guanine Transglycosylase Based on a New Unexpected Binding Mode Detected by Crystal Structure Analysis. J. Med. Chem. 46, 1133-1143.
  169. Ball, P. (2008) Water as an Active Constituent in Cell Biology. Chem. Rev. 108, 74-108.
  170. Breiten, B., Lockett, M. R., Sherman, W., Fujita, S., Al-Sayah, M., Lange, H., Bowers, C. M., Heroux, A., Krilov, G. & Whitesides, G. M. (2013) Water Networks Contribute to Enthalpy/Entropy Compensation in Protein-Ligand Binding. J. Am. Chem. Soc. 135, 15579- 15584.
  171. García-Sosa, A. T., Mancera, R. L. & Dean, P. M. (2003) WaterScore: A Novel Method for Distinguishing Between Bound and Displaceable Water Molecules in the Crystal Structure of the Binding Site of Protein-Ligand Complexes. J. Mol. Model. 9, 172-182.
  172. [143] Dunitz, J. D. (1995) Win Some, Lose Some: Enthalpy-Entropy Compensation in Weak Intermolecular Interactions. Chem. Biol. 2, 709-712.
  173. [218] Cooper, J., Quail, W., Frazao, C., Foundling, S. I., Blundell, T. L., Humblet, C., Lunney, E. A., Lowther, W. T. & Dunn, B. M. (1992) X-Ray Crystallographic Analysis of Inhibition of Endothiapepsin by Cyclohexyl Renin Inhibitors. Biochemistry 31, 8142-8150.
  174. [183] Vallee, B. L. & Auld, D. S. (1990) Zinc Coordination, Function, and Structure of Zinc Enzymes and other Proteins. Biochemistry 29, 5647-5659.

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