Correlating structure and ligand affinity in drug discovery: A cautionary tale involving second shell residues

Biological Chemistry

Volumn 395, Issue 7-8, 2014, Pages 891-903

  Tziridis, Anastasia ^a   Rauh, Daniel ^b   Neumann, Piotr ^c   Kolenko, Petr ^d   Menzel, Anja ^e   Bräuer, Ulrike ^f   Ursel, Christian ^g   Steinmetzer, Peter ^g   Stürzebecher, Jörg ^g   Schweinitz, Andrea ^g   Steinmetzer, Torsten ^h   Stubbs, Milton T ⁱ  

^a SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

^b TU DORTMUND UNIVERSITY   (Germany)

^c UNIVERSITY OF GÖTTINGEN   (Germany)

^d INSTITUTE OF MACROMOLECULAR CHEMISTRY   (Czech Republic)

^e OTTO VON GUERICKE UNIVERSITY   (Germany)

^f UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^g JENA UNIVERSITY HOSPITAL   (Germany)

^h PHILIPPS UNIVERSITY MARBURG   (Germany)

ⁱ MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

Author keywords

Crystal structure; Factor Xa; Ligand affinity; Protein flexibility; Selectivity; Structure based drug design

Indexed keywords

1 [(7 CARBAMIMIDOYLNAPHTHALEN 2 YL)METHYL] 6 (1 ETHANIMIDOYLPIPERIDIN 4 YL)OXY 2 PROPAN 2 YL INDOLE 4 CARBOXYLIC ACID; 2 [(7 CARBAMIMIDOYLNAPHTHALEN 2 YL)METHYL [4 (1 ETHANIMIDOYLPIPERIDIN 4 YL)OXYPHENYL]SULFAMOYL]ETHANOIC ACID; 2,7 BIS(4 AMIDINOBENZYLIDENE)CYCLOHEPTAN 1 ONE; 3 (3 CARBAMIMIDOYLPHENYL) N [4 (2 SULFAMOYLPHENYL)PHENYL] 1,2 OXAZOLE 4 CARBOXAMIDE; BENZAMIDINE; BENZYLSULFONYL DEXTRO ARGINYLGLYCYL 4 AMIDINOBENZYLAMIDE; BENZYLSULFONYL DEXTRO SERYL(TERT BUTYL)GLYCYL 4 AMIDINOBENZYLAMIDE; BLOOD CLOTTING FACTOR 10A; N ALPHA TOSYLGLYCYL 3 AMIDINO DEXTRO PHENYLALANINE METHYLESTER; SERINE PROTEINASE INHIBITOR; TRYPSIN; UNCLASSIFIED DRUG; [4 (6 CHLORONAPHTHALENE 2 SULFONYL)PIPERAZIN 1 YL][(3,4,5,6 TETRAHYDRO 2H 1,4')BIPYRIDINYL 4 YL]METHANONE; LIGAND;

ARTICLE; BINDING AFFINITY; CHEMICAL INTERACTION; COMPLEX FORMATION; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG DESIGN; DRUG PROTEIN BINDING; HYDROPHOBICITY; LIGAND BINDING; MOLECULAR DOCKING; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; SITE DIRECTED MUTAGENESIS; STEREOSPECIFICITY; STRUCTURE ANALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; HUMAN; METABOLISM; STRUCTURE ACTIVITY RELATION;

DRUG DISCOVERY; FACTOR XA; HUMANS; LIGANDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84904169343     PISSN: 14316730     EISSN: 14374315     Source Type: Journal    
DOI: 10.1515/hsz-2014-0158     Document Type: Article

References (43)

1. Arnaiz, D.O., Zhao, Z., Liang, A., Trinh, L., Witlow, M., Koovakkat, S.K., and Shaw, K.J. (2000). Design, synthesis, and in vitro biological activity of indole-based factor Xa inhibitors. Bioorg. Med. Chem. Lett. 10, 957-961. (Pubitemid 30301602)
2. Bailey, S. (1994). The CCP4 Suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760-763.
3. Brandstetter, H., Kühne, A., Bode, W., Huber, R., von der Saal, W., Wirthensohn, K., and Engh, R.A. (1996). X-ray structure of active site-inhibited clotting factor Xa - implications for drug design and substrate recognition. J. Biol. Chem. 271,29988-29992. (Pubitemid 26389636)
4. Brunger, A.T., Adams, P.D., Clore, G.M., Delano, W.L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.S., Kuszewski, J., Nilges, M., Pannu, N.S., et al. (1998). Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D Biol. Crystallogr. 54, 905-921.
5. Dixon, M. (1972). Graphical determination of Km and Ki. Biochem. J. 129, 197.
6. Dullweber, F., Stubbs, M.T., Musil, D., Stürzebecher, J., and Klebe, G. (2001). Factorising ligand affinity: A combined thermodynamic and crystallographic study of trypsin and thrombin inhibition. J. Mol. Biol. 313, 593-614. (Pubitemid 33052290)
7. Emsley, P. and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132. (Pubitemid 41742764)
8. Faull, A.W., Mayo, C.M., Preston, J., and Stocker, A. (1996). Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents. (Patent, WO, 9610022).
9. Feixas, F., Lindert, S., Sinko, W., and McCammon, J.A. (2014). Exploring the role of receptor flexibility in structure-based drug discovery. Biophys. Chem. 186, 31-45.
10. Hedstrom, L., Lin, T.Y., and Fast, W. (1996). Hydrophobic interactions control zymogen activation in the trypsin family of serine proteases. Biochemistry 35, 4515-4523. (Pubitemid 26113512)
11. Hirayama, F., Koshio, H., Katayama, N., Kurihara, H., Taniuchi, Y., Sato, K., Hisamichi, N., Sakai-Moritani, Y., Kawasaki, T., Matsumoto, Y., et al. (2002). The discovery of YM-60828: A potent, selective and orally-bioavailable Factor Xa inhibitor. Bioorg. Med. Chem. 10, 1509-1523. (Pubitemid 34214714)
12. Huang, S.Y., Grinter, S.Z., and Zou, X. (2010). Scoring functions and their evaluation methods for protein-ligand docking: Recent advances and future directions. Phys. Chem. Chem. Phys. 12, 12899-12908.
13. Jones, T.A., Zou, J.Y., Cowan, S.W., and Kjeldgaard, M. (1991). Improved methods for building protein models in electrondensity maps and the location of errors in these models. Acta Crystallog. Sect. A 47, 110-119.
14. Lin, Z. and Johnson, M.E. (1995). Proposed cation-p mediated binding by factor Xa: A novel enzymatic mechanism for molecular recognition. FEBS Lett. 370, 1-5.
15. Martin, S.F. and Clements, J.H. (2013). Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes. Annu. Rev. Biochem. 82, 267-293.
16. Nar, H. (2012). The role of structural information in the discovery of direct thrombin and factor Xa inhibitors. Trends Pharmacol. Sci. 33, 279-288.
17. Otwinowski, Z. and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Macromol. Crystallog. A 276, 307-326.
18. Perzborn, E., Roehrig, S., Straub, A., Kubitza, D., and Misselwitz, F. (2011). The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat. Rev. Drug Discov. 10, 61-75.
19. Pruitt, J.R., Pinto, D.J., Estrella, M.J., Bostrom, L.L., Knabb, R.M., Wong, P.C., Wright, M.R., and Wexler, R.R. (2000). Isoxazolines and isoxazoles as Factor Xa inhibitors. Bioorg. Med. Chem. Lett. 10, 685-689. (Pubitemid 30215863)
20. Rauh, D., Reyda, S., Klebe, G., and Stubbs, M.T. (2002). Trypsin mutants for structure-based drug design: expression, refolding and crystallisation. Biol. Chem. 383, 1309-1314. (Pubitemid 35215083)
21. Rauh, D., Klebe, G., Stürzebecher, J., and Stubbs, M.T. (2003). ZZ made EZ: Influence of inhibitor configuration on enzyme selectivity. J. Mol. Biol. 330, 761-770.
22. Rauh, D., Klebe, G., and Stubbs, M.T. (2004). Understanding protein-ligand interactions: the price of protein flexibility. J. Mol. Biol. 335, 1325-1341. (Pubitemid 38077249)
23. Renatus, M., Bode, W., Huber, R., Stürzebecher, J., and Stubbs, M.T. (1998). Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: Implications for the inhibition of factor Xa, tPA, and urokinase. J. Med. Chem. 41, 5445-5456.
24. Reyda, S., Sohn, C., Klebe, G., Rall, K., Ullmann, D., Jakubke, H.D., and Stubbs, M.T. (2003). Reconstructing the binding site of factor Xa in trypsin reveals ligand-induced structural plasticity. J. Mol. Biol. 325, 963-977. (Pubitemid 36266699)
25. Rose, P.W., Bi, C., Bluhm, W.F., Christie, C.H., Dimitropoulos, D., Dutta, S., Green, R.K., Goodsell, D.S., Prlic, A., Quesada, M., et al. (2013). The RCSB Protein Data Bank: new resources for research and education. Nucleic Acids Res. 41, D475-D482.
26. Salonen, L.M., Bucher, C., Banner, D.W., Haap, W., Mary, J.L., Benz, J., Kuster, O., Seiler, P., Schweizer, W.B., and Diederich, F. (2009). Cation-p interactions at the active site of factor Xa: dramatic enhancement upon stepwise N-alkylation of ammonium ions. Angew. Chem. Int. Ed. 48, 811-814.
27. Salonen, L.M., Holland, M.C., Kaib, P.S., Haap, W., Benz, J., Mary, J.L., Kuster, O., Schweizer, W.B., Banner, D.W., and Diederich, F. (2012). Molecular recognition at the active site of factor Xa: cation-pi interactions, stacking on planar peptide surfaces, and replacement of structural water. Chemistry 18, 213-222.
28. Schärer, K., Morgenthaler, M., Paulini, R., Obst-Sander, U., Banner, D.W., Schlatter, D., Benz, J., Stihle, M., and Diederich, F. (2005). Quantification of cation-pi interactions in protein-ligand complexes: crystal-structure analysis of Factor Xa bound to a quaternary ammonium ion ligand. Angew. Chem Int. Ed. 44, 4400-4404. (Pubitemid 41026381)
29. Schweinitz, A., Stürzebecher, A., Stürzebecher, U., Schuster, O., Stürzebecher, J., and Steinmetzer, T. (2006). New substrate analogue inhibitors of factor Xa containing 4-amidinobenzylamide as P1 residue: part 1. Med. Chem. 2, 349-361. (Pubitemid 44083128)
30. Shotton, D.M. and Hartley, B.S. (1970). Amino-acid sequence of porcine pancreatic elastase and its homologies with other serine proteinases. Nature 225, 802-806.
31. Sliwoski, G., Kothiwale, S., Meiler, J., and Lowe, E.W., Jr. (2014). Computational methods in drug discovery. Pharmacol. Rev. 66, 334-395.
32. Steinberg, B.A. and Becker, R.C. (2013). Structure-function relationships of factor Xa inhibitors: Implications for the practicing clinician. J Thromb. Thrombolysis. 37, 234-241.
33. Straub, A., Roehrig, S., and Hillisch, A. (2011). Oral, direct thrombin and factor Xa inhibitors: the replacement for warfarin, leeches, and pig intestines? Angew. Chem. Int. Ed. 50, 4574-4590.
34. Stubbs, M.T., Huber, R., and Bode, W. (1995). Crystal-structures of factor Xa specific inhibitors in complex with trypsin - structural grounds for inhibition of factor Xa and selectivity against thrombin. FEBS Lett. 375, 103-107.
35. Stubbs, M.T., Reyda, S., Dullweber, F., Möller, M., Klebe, G., Dorsch, D., Mederski, W.W.K.R., and Wurziger, H. (2002). pH-dependent binding modes observed in trypsin crystals: lessons for structure-based drug design. Chembiochem 3, 246-249. (Pubitemid 36004503)
36. Stürzebecher, J., Stürzebecher, U., Vieweg, H., Wagner, G., Hauptmann, J., and Markwardt, F. (1989). Synthetic inhibitors of bovine factor Xa and thrombin comparison of their anticoagulant efficiency. Thromb. Res. 54, 245-252. (Pubitemid 19140514)
37. Stürzebecher, J., Prasa, D., Hauptmann, J., Vieweg, H., and Wikström, P. (1997). Synthesis and structure-activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine. J. Med. Chem. 40, 3091-3099. (Pubitemid 27391541)
38. Stürzebecher, A., Dönnecke, D., Schweinitz, A., Schuster, O., Steinmetzer, P., Stürzebecher, U., Kotthaus, J., Clement, B., Stürzebecher, J., and Steinmetzer, T. (2007). Highly potent and selective substrate analogue factor Xa inhibitors containing D-homophenylalanine analogues as P3 residue: part 2. ChemMedChem. 2, 1043-1053.
39. Teague, S.J. (2003). Implications of protein flexibility for drug discovery. Nat. Rev. Drug Discov. 2, 527-541. (Pubitemid 37361745)
40. Turk, D., Stürzebecher, J., and Bode, W. (1991). Geometry of binding of the Na-tosylated piperidides of m-amidino-, p-amidino- and p-guanidino phenylalanine to thrombin and trypsin. X-ray crystal structures of their trypsin complexes and modeling of their thrombin complexes. FEBS Lett. 287, 133-138.
41. Weiner, M.P., Costa, G.L., Schoettlin, W., Cline, J., Mathur, E., and Bauer, J.C. (1994). Site-directed mutagenesis of doublestranded DNA by the polymerase chain-reaction. Gene 151, 119-123.
42. Whitlow, M., Arnaiz, D.O., Buckman, B.O., Davey, D.D., Griedel, B., Guilford, W.J., Koovakkat, S.K., Liang, A., Mohan, R., Phillips, G.B., et al. (1999). Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin. Acta Crystallogr. D Biol. Crystallogr. 55, 1395-1404. (Pubitemid 29395733)
43. Yeh, C.H., Fredenburgh, J.C., and Weitz, J.I. (2012). Oral direct factor Xa inhibitors. Circ. Res. 111, 1069-1078.