Investigations on lin-Benzopurines With Respect to Dissociation Behavior, Pocket Cross-Talk, Targeting Resistance Mutants, Residual Mobility, and Scaffold Optimization

The present thesis deals with the characterization and improvement of selective antibiotics targeting the enzyme tRNA–guanine transglycosylase. Recently, the lin-benzopurine scaffold was introduced as promising starting point for the structure-based design of TGT inhibitors. Two classes, namely the...

Ausführliche Beschreibung

Gespeichert in:
1. Verfasser: Neeb, Manuel
Beteiligte: Klebe, Gerhard (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2014
Pharmazeutische Chemie
Ausgabe:http://dx.doi.org/10.17192/z2014.0419
Schlagworte:
Online Zugang:PDF-Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!

1. Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685.


2. World Health Organization (2005). Guidelines for the control of shigellosis, including the epidemics which were caused by Shigella dysenteriae type 1. Department of Child and Adolescent Health and Development, Geneva.


3. http://archiv.ub.uni-marburg.de/diss/z2013/0074


4. Gasteiger, E., Hoogland, C., Gattiker, A., Duvaud, S., Wilkins, M. R., Appel, R. D., Bairoch, A. (2005). Protein Identification and Analysis Tools on the ExPASy Server. In The Proteomics Protocols Handbook; Walker, J. M., Ed.; Humana Press: Totowa, N. J.; 571-607.


5. El Tayar, N., Tsai, R.-S., Testa, B., Carrupt, P.-A., Leo, A. (1991). Partitioning of solutes in different solvent systems: The contribution of hydrogen-bonding capacity and polarity. J. Pharm. Sci. 80, 590-598.


6. Testa, B., Carrupt, P. A., Gaillard, P., Billois, F., Weber, P. (1996). Lipophilicity in Molecular Modeling. Pharm. Res. 13, 335-343.


7. Tellinghuisen, J. (2004). Statistical error in isothermal titration calorimetry. Methods Enzymol. 383, 245-282.


8. Jones, G., Willett, P., Glen, R. C., Leach, A. R., Taylor, R. (1997). Development and Validation of a Genetic Algorithm for Flexible Docking. J. Mol. Biol. 267, 727-748.


9. Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., Case, D. A. (2004). Development and Testing of a General Amber Force Field. J. Comput. Chem. 25, 1157-1174.


10. Nhieu, G. T. V., Bourdet-Sicard, R., Duménil, G., Blocker, A., Sansonetti, P. J. (2000). Bacterial signals and cell responses during Shigella entry into epithelial cells. Cell. Microbiol. 2, 187-193.


11. Word, J. M., Lovell, S. C., Richardson, J. S., Richardson, D. C. (1999). Asparagine and Glutamine: Using Hydrogen Atom Contacts in the Choice of Side-Chain Amide Orientation. J. Mol. Biol. 285, 1735-1747.


12. Seidler, J., McGovern, S. L., Doman, T. N., Shoichet, B. K. (2003). Identification and Prediction of Promiscuous Aggregating Inhibitors among Known Drugs. J. Med. Chem. 46, 4477-4486.


13. Ritschel, T., Kohler, P. C., Neudert, G., Heine, A., Diederich, F., Klebe, G. (2009). How to Replace the Residual Solvation Shell of Polar Active Site Residues to Achieve Nanomolar Inhibition of tRNA-Guanine Transglycosylase. ChemMedChem 4, 2012-2023.


14. Velazquez-Campoy, A., Kiso, Y., Freire, E. (2001). The Binding Energetics of First-and Second- Generation HIV-1 Protease Inhibitors: Implications for Drug Design. Arch. Biochem. Biophys. 390, 169-175.


15. Barken, F. M., Gasteiger, E. L. (1980). Excitability of a penicillin-induced cortical epileptic focus. Exp. Neurol. 70, 539-547.


16. Mizoue, L. S., Tellinghuisen, J. (2004). The role of backlash in the "first injection anomaly" in isothermal titration calorimetry. Anal. Biochem. 326, 125-127.


17. Tellinghuisen, J. (2007). Calibration in isothermal titration calorimetry: Heat and cell volume from heat of dilution of NaCl(aq). Anal. Biochem. 360, 47-55.


18. Tellinghuisen, J., Chodera, J. D. (2011). Systematic errors in isothermal titration calorimetry: Concentrations and baselines. Anal. Biochem. 414, 297-299.


19. Raffa, R. B., Stagliano, G. W., Spencer, S. D. (2004). Protonation effect on drug affinity. Eur. J. Pharmacol. 483, 323-324.


20. Rauh, D., Klebe, G., Stubbs, M. T. (2004). Understanding Protein-Ligand Interactions: The Price of Protein Flexibility. J. Mol. Biol. 335, 1325–1341.


21. Brenk, R., Meyer, E. A., Reuter, K., Stubbs, M. T., Garcia, G. A., Diederich, F., Klebe, G. (2004). Crystallographic Study of Inhibitors of tRNA-guanine Transglycosylase Suggests a New Strucutre-Based Pharmacophore for Virtual Screening. J. Mol. Biol. 338, 55-75.


22. Czodrowski, P., Sotriffer, C. A., Klebe, G. (2007). Protonation Changes upon Ligand Binding to Trypsin and Thrombin: Structural Interpretation Based on pK a Calculations and ITC Experiments. J. Mol. Biol. 367, 1347-1356.


23. Steuber, H., Czodrowski, P., Sotriffer, C. A., Klebe, G. (2007). Tracing Changes in Protonation: A Prerequisite to Factorize Thermodynamic Data of Inhibitor Binding to Aldose Reductase. J. Mol. Biol. 373, 1305-1320.


24. Baum, B., Mohamed, M., Zayed, M., Gerlach, C., Heine, A., Hangauer, D., Klebe, G. (2009). More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin. J. Mol. Biol. 390, 56-69.


25. Tellinghuisen, J. (2003). A study of statistical error in isothermal titration calorimetry. Anal. Biochem. 321, 79-88.


26. Iwata-Reuyl, D. (2003). Biosynthesis of the 7-deazaguanosine hypermodified nucleosides of transfer RNA. Bioorg. Chem. 31, 24-43.


27. Kupke, D. W., Dorrier, T. E. (1978). Protein concentration measurements: the dry weight. Methods Enzymol. 48, 155–162.


28. Koeppe, R. E. II, Stroud, R. M. (1976). Mechanism of hydrolysis by serine proteases: direct determination of the pK a 's of aspartyl-102 and aspartyl-194 in bovine trypsin using difference infrared spectroscopy. Biochemistry 15, 3450–3458.


29. Robinson, N. C., Tye, R. W., Neurath, H., Walsh, K. A. (1971). Isolation of Trypsins by Affinity Chromatography. Biochemistry 10, 2743–2747.


30. Lee, B. W., 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.


31. McCarty, R. M., Somogyi, A., Bandarian, V. (2009). Escherichia coli QueD Is a 6-Carboxy-5,6,7,8- tetrahydropterin Synthase. Biochemistry 48, 2301-2303.


32. Romier, C., Reuter, K., Suck, D., Ficner, R. (1996). Mutagenesis and Crystallographic Studies of Zymomonas mobilis tRNA-Guanine Transglycosylase Reveal Aspartate 102 as the Active Site Nucleophile. Biochemistry 35, 15734-15739.


33. Spencer, J. N., Gleim, J. E., Blevins, C. H., Garrett, R. C., Mayer, F. J. (1979). Enthalpies of Solution and Transfer Enthalpies -Analysis of the Pure Base Calorimetric Method for the Determination of Hydrogen-Bond Enthalpies. J. Phys. Chem. 83, 1249-1255.


34. Dalvit, C., Fasolini, M., Flocco, M., Knapp, S., Pevarello, P., Veronesi, M. (2002). NMR-Based Screening with Competition Water-Ligand Observed via Gradient Spectroscopy Experiments: Detection of High-Affinity Ligands. J. Med. Chem. 45, 2610-2614.


35. Makara, G. M. (2007). On Sampling of Fragment Space. J. Med. Chem. 50, 3214-3221.


36. Xie, W., Liu, X., Huang, R. H. (2003). Chemical trapping and crystal structure of a catalytic tRNA guanine transglycosylase covalent intermediate. Nat. Struct. Biol. 10, 781-788.


37. 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.


38. Levine, O. S., Levine, M. M. (1991). Houseflies (Musca domestica) as Mechanical Vectors of Shigellosis. Rev. Infect. Dis. 13, 688-696.


39. Ashkenazi, S., Levy, I., Kazaronovski, V., Samra, Z. (2003). Growing antimicrobial resistance of Shigella isolates. J. Antimicrob. Chemother. 51, 427-429.


40. Escobar-Páramo, P., Clermont, O., Blanc-Potard, A. B., Bui, H., Le Bouguénec, C., Denamur, E. (2004). A Specific Genetic Background Is Required for Acquisition and Expression of Virulence Factors in Escherichia coli. Mol. Biol. Evol. 21, 1085-1094.


41. 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.


42. Liang, Y. (2008). Applications of isothermal titration calorimetry in protein science. Acta Biochim. Biophys. Sin. 40, 565–576.


43. Martin, S. F., Clements, J. H. (2013). Correlating Structure and Energetics in Protein-Ligand Interactions: Paradigms and Paradoxes. Annu. Rev. Biochem. 82, 267-293.


44. Rauh, D., Reyda, S., Klebe, G., Stubbs, M. T. (2002). Trypsin Mutants for Structure-Based Drug Design: Expression, Refolding and Crystallisation. Biol. Chem. 383, 1309–1314.


45. Baranauskienė, L., Petrikaitė, V., Matulienė, J., Matulis, D. (2009). Titration Calorimetry Standards and the Precision of Isothermal Titration Calorimetry Data. Int. J. Mol. Sci. 10, 2752-2762.


46. Brown, A. (2009). Analysis of Cooperativity by Isothermal Titration Calorimetry. Int. J. Mol. Sci. 10, 3457–3477.


47. Daviter, T., Fronzes, R. (2013). Protein Sample Characterization. Methods Mol. Biol. 1008, 35-62.


48. Sansonetti, P. J. (2001). Rupture, invasion and inflammatory destruction of the intestinal barrier by Shigella, making sense of prokaryote-eukaryote cross-talks. FEMS Microbiol. Rev. 25, 3-14.


49. Jennison, A. V., Verma, N. K. (2004). Shigella flexneri infection: pathogenesis and vaccine development. FEMS Microbiol. Rev. 28, 43-58.


50. Yonemura, H., Imamura, T., Soejima, K., Nakahara, Y., Morikawa, W., Ushio, Y., Kamachi, Y., Nakatake, H., Sugawara, K., Nakagaki, T., Nozaki, C. (2004). Preparation of Recombinant α-Thrombin: High-Level Expression of Recombinant Human Prethrombin-2 and Its Activation by Recombinant Ecarin. J. Biochem. 135, 577–582.


51. Perspicace, S., Banner, D., Benz, J., Müller, F., Schlatter, D., Huber, W. (2009). Fragment-Based Screening Using Surface Plasmon Resonance Technology. J. Biomol. Screen. 14, 337-349.


52. Eldridge, M. D., Murray, C. W., Auton, T. R., Paolini, G. V., Mee, R. P. (1997). Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comput. Aided Mol. Des. 11, 425-445.


53. Goa, J. (1953). A Micro Biuret Method for Protein Determination; Determination of Total Protein in Cerebrospinal Fluid. Scand. J. Clin. Lab. Invest. 5, 218–222.


54. Connolly, M. L. (1983). Analytical Molecular Surface Calculation. J. Appl. Crystallogr. 16, 548-558.


55. Ritschel, T., Atmanene, C., Reuter, K., Van Dorsselaer, A., Sanglier-Cianferani, S., Klebe, G. (2009). An Integrative Approach Combining Noncovalent Mass Spectrometry, Enzyme Kinetics and X-ray Crystallography to Decipher Tgt Protein-Protein and Protein-RNA Interaction. J. Mol. Biol. 393, 833-847.


56. Bashford, D. (1997). An Object-Oriented Programming Suite for Electrostatic Effects in Biological Molecules. An Experience Report on the MEAD Project. In Scientific Computing in Object- Oriented Parallel Environments; Ishikawa, Y., Oldehoeft, R., Reynders, J., Tholburn, M., Eds.; Springer: Berlin / Heidelberg.; 1343: 233-240.


57. Thorn, A., Sheldrick, G. M. (2011). ANODE: anomalous and heavy-atom density calculation. J. Appl. Crystallogr. 44, 1285-1287.


58. Sack, R. B., Rahman, M., Yunus, M., Khan, E. H. (1997). Antimicrobial Resistance in Organisms Causing Diarrheal Disease. Clin. Infect. Dis. 24 Suppl. 1, S102-105.


59. Kleywegt, G. J., Zou J. Y., Kjeldgaard M. & Jones T. A. (2001). Around O. In International Tables for Crystallography; M. G. Rossmann, Arnold, E., Eds.; Kluwer Academic Publishers: Dordrecht; Vol. F, 353-356.


60. Congreve, M., Carr, R., Murray, C., Jhoti, H. (2003). A 'Rule of Three' for fragment-based lead discovery? Drug Discov. Today 8, 876-877.


61. Sheldrick, G. M. (2008). A short history of SHELX. Acta Cryst. A 64, 112-122.


62. Bensadoun, A., Weinstein, D. (1976). Assay of Proteins in the Presence of Interfering Materials. Anal. Biochem. 70, 241–250.


63. 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 Structure–Activity Relationship for Inhibition of a tRNA-Modifying Enzyme. J. Med. Chem. 57, 5566-5578.


64. Gill, S. C., von Hippel, P. H. (1989). Calculation of Protein Extinction Coefficients from Amino Acid Sequence Data. Anal. Biochem. 182, 319–326.


65. Chaires, J. B. (2008). Calorimetry and Thermodynamics in Drug Design. Annu. Rev. Biophys. 37, 135– 151.


66. Neeb, M., Czodrowski, P., Heine, A., Barandun, L. J., Hohn, C., Diederich, F., Klebe, G. (2014). Chasing Protons: How Isothermal Titration Calorimetry, Mutagenesis and pK a Calculations Trace the Locus of Charge in Ligand Binding to a tRNA-Binding Enzyme. J. Med. Chem. 57, 5554-5565.


67. Hornak, V., Abel, R., Okur, A., Strockbine, B., Roitberg, A., Simmerling, C. (2006). Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters. Proteins 65, 712-725.


68. Hall, H. K. (1957). Correlation of the Base Strengths of Amines. J. Am. Chem. Soc. 79, 5441-5444.


69. Ritschel, T., Hoertner, S., Heine, A., Diederich, F., Klebe, G. (2009). Crystal Structure Analysis and in Silico pK a Calculations Suggest Strong pK a Shifts of Ligands as Driving Force for High-Affinity Binding to TGT. ChemBioChem 10, 716-727.


70. 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.


71. Lipinski, C. A., Lombardo, F., Dominy, B. W., Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3-26.


72. Jakalian, A., Bush, B. L., Jack, D. B., Bayly, C. I. (2000). Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model: I. Method. J. Comput. Chem. 21, 132-146.


73. Neudert, G., Klebe, G. (2011). fconv: format conversion, manipulation and feature computation of molecular data. Bioinformatics 27, 1021-1022.


74. 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. Chembiochem 4, 1066-1077.


75. 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.


76. 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 lin- Benzohypoxanthines as Ligands for Zymomonas mobilis tRNA-Guanine Transglycosylase: Replacement of Protein-Ligand Hydrogen Bonding by Importing Water Clusters. Chem. Eur. J. 18, 9246-9257.


77. Kotloff, K. L., Winickoff, J. P., Ivanoff, B., Clemens, J. D., Swerdlow, D. L., Sansonetti, P. J., Adak, G. K., Levine, M. M. (1999). Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull. World Health Organ. 77, 651- 666.


78. Christensen, J. J., Hansen, L. D., Izatt, R. M. (1976). Handbook of Proton Ionization Heats and Related Thermodynamic Quantities; Wiley-Interscience: New York.


79. Kohler, P. C., Ritschel, T., Schweizer, W. B., Klebe, G., Diederich, F. (2009). High-Affinity Inhibitors of tRNA-Guanine Transglycosylase Replacing the Function of a Structural Water Cluster. Chem. Eur. J. 15, 10809-10817.


80. 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 Cryst. D 69, 1798-1807.


81. Velazquez-Campoy, A., Todd, M. J., Freire, E. (2000). HIV-1 Protease Inhibitors: Enthalpic versus Entropic Optimization of the Binding Affinity. Biochemistry. 39, 2201-2207.


82. 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.


83. Battye, T. G. G., Kontogiannis, L., Johnson, O., Powell, H. R., Leslie, A. G. W. (2011). iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Acta Cryst. D 67, 271-281.


84. Jorgensen, W. L., Pranata, J. (1990). Importance of Secondary Interactions in Triply Hydrogen-Bonded Complexes -Guanine-Cytosine vs Uracil-2,6-Diaminopyridine. J. Am. Chem. Soc. 112, 2008- 2010.


85. DuPont, H. L., Levine, M. M., Hornick, R. B., Formal, S. B. (1989). Inoculum Size in Shigellosis and Implications for Expected Mode of Transmission. J. Infect. Dis. 159, 1126-1128.


86. 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.


87. McGovern, S. L., Shoichet, B. K. (2003). Kinase Inhibitors: Not Just for Kinases Anymore. J. Med. Chem. 46, 1478-1483.


88. Burnouf, D., Ennifar, E., Guedich, S., Puffer, B., Hoffmann, G., Bec, G., Disdier, F., Baltzinger, M., Dumas, P. (2012). kinITC: A New Method for Obtaining Joint Thermodynamic and Kinetic Data by Isothermal Titration Calorimetry. J. Am. Chem. Soc. 134, 559-565. References Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., Onufriev, A., Simmerling, C., Wang, B., Woods, R. J. (2005). The Amber Biomolecular Simulation Programs. J. Comput. Chem. 26, 1668-1688.


89. Biela, A., Sielaff, F., Terwesten, F., Heine, A., Steinmetzer, T., Klebe, G. (2012). Ligand Binding Stepwise Disrupts Water Network in Thrombin: Enthalpic and Entropic Changes Reveal Classical Hydrophobic Effect. J. Med. Chem. 55, 6094-6110.


90. Zhang, Y. L., Zhang, Z. Y. (1998). Low-Affinity Binding Determined by Titration Calorimetry Using a High-Affinity Coupling Ligand: A Thermodynamic Study of Ligand Binding to Protein Tyrosine Phosphatase 1B. Anal. Biochem. 261, 139-148. Publications and Poster Presentations Publications


91. Wang, W. (2000). Lyophilization and development of solid protein pharmaceuticals. Int. J. Pharm. 203, 1–60.


92. Holdgate, G. A. (2001). Making Cool Drugs Hot: Isothermal Titration Calorimetry as a Tool to Study Binding Energetics. BioTechniques 31, 164–184.


93. Sansonetti, P. J. (2001). Microbes and Microbial Toxins: Paradigms for Microbial-Mucosal Interactions III. Shigellosis: from symptoms to molecular pathogenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G319-323.


94. Sambrook, J. F., Russell, D. W. (2001). Molecular Cloning: A Laboratory Manual (3 rd Ed.); Cold Spring Harbor Laboratory Press: New York.


95. Wadsö, I. (2000). Needs for standards in isothermal microcalorimetry. Thermochim. Acta 347, 73-77.


96. Frey, B., McCloskey, J., Kersten, W., Kersten, H. (1988). New Function of Vitamin B 12 : Cobamide- Dependent Reduction of Epoxyqueuosine to Queuosine in tRNAs of Escherichia coli and Salmonella typhimurium. J. Bacteriol. 170, 2078-2082.


97. Murray, T. J., Zimmerman, S. C. (1992). New Triply Hydrogen-Bonded Complexes with Highly Variable Stabilities. J. Am. Chem. Soc. 114, 4010-4011.


98. Jakobi, S. (2013). Nichtkompetitive Inhibition der tRNA-Guanin Transglycosylase durch Störung der essentiellen Protein-Protein-Interaktion. Dissertation, Philipps-Universität Marburg.


99. Frølund, B., Jørgensen, A. T., Tagmose, L., Stensbøl, T. B., Vestergaard, H. T., Engblom, C., Kristiansen, U., Sanchez, C., Krogsgaard-Larsen, P., Liljefors, T. (2002). Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA A Antagonists: Synthesis, Pharmacology, and Molecular Modeling. J. Med. Chem. 45, 2454-2468.


100. Ryckaert, J. P., Ciccotti, G., Berendsen, H. J. C. (1977). Numerical-Integration of Cartesian Equations of Motion of a System with Constraints -Molecular-Dynamics of n-Alkanes. J. Comput. Phys. 23, 327-341.


101. Schanker, L. S. (1962). Passage of Drugs Across Body Membranes. Pharmacol. Rev. 14, 501-530. References Schmitt, P., Poiger, T., Simon, R., Freitag, D., Kettrup, A., Garrison, A. W. (1997). Simultaneous Determination of Ionization Constants and Isoelectric Points of 12 Hydroxy-s-Triazines by Capillary Zone Electrophoresis and Capillary Isoelectric Focusing. Anal. Chem. 69, 2559-2566.


102. Hörtner, S. R., Ritschel, T., Stengl, B., Kramer, C., Schweizer, W. B., Wagner, B., Kansy, M., Klebe, G., Diederich, F. (2007). Potent Inhibitors of tRNA-Guanine Transglycosylase, an Enzyme Linked to the Pathogenicity of the Shigella Bacterium: Charge-Assisted Hydrogen Bonding. Angew.


103. Otwinowski, Z., Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326.


104. Laskowski, R. A., MacArthur, M. W., Moss, D. S., Thornton, J. M. (1993). PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Cryst. 26, 283-291.


105. Protease Inhibition: A Plausible Hypothesis. Biochemistry 37, 5791-5797.


106. 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 24, 516-519.


107. Bradford, M. M. (1976). Rapid and Sensitive Method for Quantitation of Microgram Quantities of Protein Utilizing Principle of Protein-Dye Binding. Anal. Biochem. 72, 248-254.


108. 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.


109. Sansonetti, P. J., Bergounioux, J. (2008). Shigellosis. In Harrison's Principles of Internal Medicine (17 th Ed.); Fauci, A. S., Braunwald, E., Kasper, D. L., Hauser, S. L., Longo, D. L., Jameson, J. L., Loscalzo, J., Eds.; McGraw-Hill: New York; 962-964.


110. Erickson, J. W., Burt, S. K. (1996). Structural Mechanisms of HIV Drug Resistance. Annu. Rev. Pharmacol. Toxicol. 36, 545-571.


111. Pang, Y. P. (2001). Successful Molecular Dynamics Simulation of Two Zinc Complexes Bridged by a Hydroxide in Phosphotriesterase Using the Cationic Dummy Atom Method. Proteins 45, 183- 189.


112. 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.


113. Ritschel, T. (2009). TGT a Drug Target to Study pKa Shifts, Residual Solvation & Protein -Protein Interface Formation. Dissertation, Philipss-Universität Marburg.


114. Allen, F. H. (2002). The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Cryst. B 58, 380-388.


115. McCarty, R. M., Somogyi, A., Lin, G., Jacobsen, N. E., Bandarian, V. (2009). The Deazapurine Biosynthetic Pathway Revealed: In Vitro Enzymatic Synthesis of PreQ 0 from Guanosine 5'- Triphosphate in Four Steps. Biochemistry 48, 3847-3852.


116. Conradi, R. A., Hilgers, A. R., Ho, N. F., Burton, P. S. (1991). The Influence of Peptide Structure on Transport Across Caco-2 Cells. Pharm. Res. 8, 1453-1460.


117. Durand, J. M., Björk, G. R., Kuwae, A., Yoshikawa, M., Sasakawa, C. (1997). The Modified Nucleoside 2-Methylthio-N 6 -Isopentenyladenosine in tRNA of Shigella flexneri Is Required for Expression of Virulence Genes. J. Bacteriol. 179, 5777-5782.


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


119. Curnow, A. W., Garcia, G. A. (1995). tRNA-guanine transglycosylase from Escherichia coli. Minimal tRNA structure and sequence requirements for recognition. J. Biol. Chem. 270, 17264-17267.


120. 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.


121. Durand, J. M., 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.


122. Klebe, G. (2009). Wirkstoffdesign -Entwurf und Wirkung von Arzneistoffen. 2. Auflage; Spektrum Akademischer Verlag: Heidelberg.


123. 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 33, 159-166.


124. Verdonk, M. L., Rees, D. C. (2008). Group Efficiency: A Guideline for Hits-to-Leads Chemistry. ChemMedChem 3, 1179-1180.


125. Czodrowski, P., Dramburg, I., Sotriffer, C. A., Klebe, G. (2006). Development, validation, and application of adapted PEOE charges to estimate pK a values of functional groups in protein- ligand complexes. Proteins 65, 424-437.


126. 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.


127. Turnbull, W. B., Daranas, A. H. (2003). On the Value of c: Can Low Affinity Systems Be Studied by Isothermal Titration Calorimetry? J. Am. Chem. Soc. 125, 14859–14866.


128. Coan, K. E. D., Shoichet, B. K. (2008). Stoichiometry and Physical Chemistry of Promiscuous Aggregate-Based Inhibitors. J. Am. Chem. Soc. 130, 9606-9612.


129. McGovern, S. L., Caselli, E., Grigorieff, N., Shoichet, B. K. (2002). A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening. J. Med. Chem. 45, 1712- 1722.


130. Feng, B. Y., Simeonov, A., Jadhav, A., Babaoglu, K., Inglese, J., Shoichet, B. K., Austin, C. P. (2007). A High-Throughput screen for Aggregation-Based Inhibition in a Large Compound Library. J. Med. Chem. 50, 2385-2390.


131. Tellinghuisen, J. (2005). Optimizing Experimental Parameters in Isothermal Titration Calorimetry: Variable Volume Procedures. J. Phys. Chem. B 109, 20027-20035.


132. Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., Klein, M. L. (1983). Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926-935.


133. Darden, T., York, D., Pedersen, L. (1993). Particle mesh Ewald -an N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089-10092.


134. Emsley, P., Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Cryst. D 60, 2126-2132.


135. Painter, J., Merritt, E. A. (2006). Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta Cryst. D 62, 439-450.


136. Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G., McCoy, A., McNicholas, S. J., Murshudov, G. N., Pannu, N. S., Potterton, E. A., Powell, H. R., Read, R. J., Vagin, A., Wilson, K. S. (2011). Overview of the CCP4 suite and current developments. Acta Cryst. D 67, 235-242.


137. Biela, A., Khayat, M., Tan, H., Kong, J., Heine, A., Hangauer, D., Klebe, G. (2012). Impact of Ligand and Protein Desolvation on Ligand Binding to the S1 Pocket of Thrombin. J. Mol. Biol. 418, 350- 366.


138. Biela, A., Nasief, N. N., Betz, M., Heine, A., Hangauer, D., Klebe, G. (2013). Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin. Angew. Chem. Int. Ed. 52, 1822–1828.


139. Baum, B., Muley, L., Smolinski, M., Heine, A., Hangauer, D., Klebe, G. (2010). Non-Additivity of Functional Group Contributions in Protein-Ligand Binding: A Comprehensive Study by Crystallography and Isothermal Titration Calorimetry. J. Mol. Biol. 397, 1042-1054.


140. Jakobi, S., Nguyen, T. X., Debaene, F., Metz, A., Sanglier-Cianferani, S., Reuter, K., Klebe, G. (2014). Hot-spot analysis to dissect the functional protein-protein interface of a tRNA-modifying enzyme. Proteins, in press.


141. Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.- W., Kapral, G. J., Grosse-Kunstleve, R. W., McCoy, A. J., Moriarty, N. W., Oeffner, R., Read, R. J., Richardson, D. C., Richardson, J. S., Terwilliger, T. C., Zwart, P. H. (2010). PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Cryst. D 66, 213-221.


142. Feng, B. Y., Shelat, A., Doman, T. N., Guy, R. K., Shoichet, B. K. (2005). High-throughput assays for promiscuous inhibitors. Nat. Chem. Biol. 1, 146-148.


143. Tsamaloukas, A. D., Keller, S., Heerklotz, H. (2007). Uptake and release protocol for assessing membrane binding and permeation by way of isothermal titration calorimetry. Nat. Protoc. 2, 695-704.


144. Ladbury, J. E., Klebe, G., Freire, E. (2010). Adding calorimetric data to decision making in lead discovery: a hot tip. Nat. Rev. Drug Discov. 9, 23-27.


145. Navratilova, I., Hopkins, A. L. (2010). Fragment Screening by Surface Plasmon Resonance. ACS Med. Chem. Lett. 1, 44-48.


146. Baker, B. M., Murphy, K. P. (1996). Evaluation of Linked Protonation Effects in Protein Binding Reactions Using Isothermal Titration Calorimetry. Biophys. J. 71, 2049-2055.


147. Dixon, M. (1953). The Determination of Enzyme Inhibitor Constants. Biochem. J. 55, 170-171.


148. Feng, B. Y., Shoichet, B. K. (2006). A detergent-based assay for the detection of promiscuous inhibitors. Nat. Protoc. 1, 550-553.


149. 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.


150. Kuntz, I. D., Chen, K., Sharp, K. A., Kollman, P. A. (1999). The maximal affinity of ligands. Proc. Natl. Acad. Sci. USA 96, 9997-10002.


151. 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.


152. Myszka, D. G., Abdiche, Y. N., Arisaka, F., Byron, O., Eisenstein, E., Hensley, P., Thomson, J. A., Lombardo, C. R., Schwarz, F., Stafford, W., Doyle, M. L. (2003). The ABRF-MIRG'02 Study: Assembly State, Thermodynamic, and Kinetic Analysis of an Enzyme/Inhibitor Interaction. J. Biomol. Tech. 14, 247-269.


153. McCoy, A. J. (2007). Solving structures of protein complexes by molecular replacement with Phaser. Acta Cryst. D 63, 32-41.


154. 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.


155. Doak, A. K., Wille, H., Prusiner, S. B., Shoichet, B. K. (2010). Colloid Formation by Drugs in Simulated Intestinal Fluid. J. Med. Chem. 53, 4259-4265.


156. Thorne, N., Auld, D. S., Inglese, J. (2010). Apparent activity in high-throughput screening: origins of compound-dependent assay interference. Curr. Opin. Chem. Biol. 14, 315-324.


157. Snyder, P. W., Mecinovid, J., Moustakas, D. T., Thomas, S. W., 3rd, Harder, M., Mack, E. T., Lockett, M. R., Héroux, A., Sherman, W., Whitesides, G. M. (2011). Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc. Natl. Acad. Sci. USA 108, 17889-17894.


158. Mandal, J., Ganesh, V., Emelda, J., Mahadevan, S., Parija, S. C. (2012). The Recent Trends of Shigellosis: A JIPMER Perspective. J. Clin. Diagn. Res. 6, 1474-1477.


159. King, N. M., Prabu-Jeyabalan, M., Bandaranayake, R. M., Nalam, M. N., Nalivaika, E. A., Özen, A., Haliloğlu, T., Yilmaz, N. K., Schiffer, C. A. (2012). Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease. ACS Chem. Biol. 7, 1536-1546.


160. Biela, I., Tidten-Luksch, N., Immekus, F., Glinca, S., Nguyen, T. X. P., Gerber, H.-D., Heine, A., Klebe, G., Reuter, K. (2013). Investigation of Specificity Determinants in Bacterial tRNA-Guanine Transglycosylase Reveals Queuine, the Substrate of Its Eucaryotic Counterpart, as Inhibitor. PloS One 8, e64240.


161. 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.


162. Berrien, J.-F., Ourévitch, M., Morgant, G., Ghermani, N. E., Crousse, B., Bonnet-Delpon, D. (2007). A crystalline H-bond cluster of hexafluoroisopropanol (HFIP) and piperidine -Structure determination by X ray diffraction. J. Fluor. Chem. 128, 839-843.


163. 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.


164. Dullweber, F., Stubbs, M. T., Musil, Đ., Stürzebecher, J., Klebe, G. (2001). Factorising Ligand Affinity: A Combined Thermodynamic and Crystallographic Study of Trypsin and Thrombin Inhibition. J. Mol. Biol. 313, 593-614.


165. Rauh, D., Klebe, G., Stürzebecher, J., Stubbs, M. T. (2003). ZZ Made EZ: Influence of Inhibitor Configuration on Enzyme Selectivity. J. Mol. Biol. 330, 761–770.


166. Baum, B., Muley, L., Heine, A., Smolinski, M., Hangauer, D., Klebe, G. (2009). Think Twice: Understanding the High Potency of Bis(phenyl)methane Inhibitors of Thrombin. J. Mol. Biol. 391, 552-564.


167. Bogan, A. A., Thorn, K. S. (1998). Anatomy of Hot Spots in Protein Interfaces. J. Mol. Biol. 280, 1-9.


168. Freyer, M. W., Lewis, E. A. (2008). Isothermal Titration Calorimetry: Experimental Design, Data Analysis, and Probing Macromolecule/Ligand Binding and Kinetic Interactions. Methods Cell Biol. 84, 79–113.


169. Kunz, W., Henle, J., Ninham, B. W. (2004). 'Zur Lehre von der Wirkung der Salze' (about the science of the effect of salts): Franz Hofmeister's historical papers. Curr. Opin. Colloid. In. 9, 19-37.


170. 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.


171. World Health Organization (2001). Antimicrobial resistance in shigellosis, cholera and campylobacteriosis. WHO/CDS/CSR/DRS/2001.8. Department of Communicable Disease Surveillance and Response, Geneva.


172. Henry, C. M. (2001). Structure-Based Drug Design. Chem. Eng. News 79, 69-74.