Hot spot analysis for driving the development of hits into leads in fragment-based drug discovery

Journal of Chemical Information and Modeling

Volumn 52, Issue 1, 2012, Pages 199-209

  Hall, David R ^a   Ngan, Chi Ho ^a   Zerbe, Brandon S ^a   Kozakov, Dima ^a   Vajda, Sandor ^a,b  

^a Boston University   (United States)

^b Boston University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EFFICIENCY; LIGANDS; MAPPING; PROTEINS;

BOUND STRUCTURE; CORE MOIETY; DRUG DESIGN; DRUG DISCOVERY; MOLECULAR PROBES; PROTEIN MAPPING; SECONDARY HOT SPOTS; SUBSITES;

PROBES;

BIOLOGICAL PRODUCT; LIGAND; PROTEIN;

ARTICLE; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER AIDED DESIGN; DRUG ANTAGONISM; DRUG DESIGN; DRUG DEVELOPMENT; DRUG POTENTIATION; HUMAN; IC 50; METHODOLOGY; MOLECULAR PROBE; PROTEIN BINDING; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

BINDING SITES; BIOLOGICAL AGENTS; COMPUTER-AIDED DESIGN; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG DISCOVERY; HUMANS; INHIBITORY CONCENTRATION 50; LIGANDS; MODELS, MOLECULAR; MOLECULAR PROBES; PROTEIN BINDING; PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84858044079     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci200468p     Document Type: Article

References (63)

1. Erlanson, D. A.; McDowell, R. S.; O'Brien, T. Fragment-based drug discovery. J. Med. Chem. 2004, 47, 3463-3482. (Pubitemid 38822007)
2. Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragmentbased lead discovery. Nat. Rev. Drug Discovery 2004, 3, 660-672.
3. Murray, C. W.; Blundell, T. L. Structural biology in fragmentbased drug design. Curr. Opin. Struct. Biol. 2010, 20, 497-507.
4. Hubbard, R. E.; Murray, J. B. Experiences in fragment-based lead discovery. Methods Enzymol. 2011, 493, 509-531.
5. Coyne, A. G.; Scott, D. E.; Abell, C. Drugging challenging targets using fragment-based approaches. Curr. Opin. Chem. Biol. 2010, 14, 299-307.
6. Joseph-McCarthy, D. Challenges of fragment screening. J. Comput.-Aided Mol. Des. 2009, 23, 449-451.
7. Foloppe, N. The benefits of constructing leads from fragment hits. Future Med. Chem. 2011, 3, 1111-1115.
8. Loving, K.; Alberts, I.; Sherman, W. Computational approaches for fragment-based and de novo design. Curr. Top. Med. Chem. 2010, 10, 14-32.
9. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent developments in fragment-based drug discovery. J. Med. Chem. 2008, 51, 3661-3680. (Pubitemid 351956496)
10. Hajduk, P. J.; Greer, J. A decade of fragment-based drug design: Strategic advances and lessons learned. Nat. Rev. Drug Discovery 2007, 6, 211-219. (Pubitemid 46344625)
11. Murray, C. W.; Rees, D. C. The rise of fragment-based drug discovery. Nat. Chem. 2009, 1, 187-192.
12. Wells, J.; McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 2007, 450, 1001-1009. (Pubitemid 350273630)
13. Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal affinity of ligands. Proc. Nat. Acad. Sci.U.S.A. 1999, 96, 9997-10002. (Pubitemid 29422500)
14. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: A useful metric for lead selection. Drug Discovery Today 2004, 9, 430-431. (Pubitemid 38510559)
15. Hajduk, P. J.; Huth, J. R.; Fesik, S. W. Druggability indices for protein targets derived from NMR-based screening data. J. Med. Chem. 2005, 48, 2518-2525. (Pubitemid 40516441)
16. Liepinsh, E.; Otting, G. Organic solvents identify specific ligand binding sites on protein surfaces. Nat. Biotechnol. 1997, 15, 264-268. (Pubitemid 27118272)
17. Allen, K. N.; Bellamacina, C. R.; Ding, X.; Jeffery, C. J.; Mattos, C.; Petsko, G. A.; Ringe, D. An Experimental approach to mapping binding surfaces of crystalline proteins. J. Phys. Chem. 1996, 100, 2605-2611. (Pubitemid 126793213)
18. Mattos, C.; Ringe, D. Locating and characterizing binding sites on proteins. Nat. Biotechnol. 1996, 14, 595-599. (Pubitemid 26135122)
19. English, A. C.; Done, S. H.; Caves, L. S.; Groom, C. R.; Hubbard, R. E. Locating interaction sites on proteins: The crystal structure of thermolysin soaked in 2% to 100% isopropanol. Proteins 1999, 37, 628-640.
20. English, A. C.; Groom, C. R.; Hubbard, R. E. Experimental and computational mapping of the binding surface of a crystalline protein. Protein Eng. 2001, 14, 47-59. (Pubitemid 32318937)
21. Brenke, R.; Kozakov, D.; Chuang, G.; Beglov, D.; Hall, D.; Landon, M. R.; Mattos, C.; Vajda, S. Fragment-based identification of druggable "hot spots" of proteins using Fourier domain correlation techniques. Bioinformatics 2009, 25, 621-627.
22. Landon, M. R.; Lancia, D. R.; Yu, J.; Thiel, S. C.; Vajda, S. Identification of hot spots within druggable binding regions by computation solvent mapping proteins. J. Med. Chem. 2007, 50, 1231-1240. (Pubitemid 46496323)
23. Chuang, G.; Kozakov, D.; Brenke, R.; Beglov, D.; Guarnieri, F.; Vajda, S. Binding hot spots and amantadine orientation in the influenza A virus M2 proton channel. Biophys. J. 2009, 97, 2846-2853.
24. Landon, M. R.; Lieberman, R. L.; Hoang, Q. Q.; Ju, S.; Caaveiro, J. M. M.; Orwig, S. D.; Kozakov, D.; Brenke, R.; Chuang, G. Y.; Beglov, D.; Vajda, S.; Petsko, G. A.; Ringe, D. Detection of ligand binding hot spots on protein surfaces via fragment-based methods: Application to DJ-1 and glucocerebrosidase. J. Comput.-Aided Mol. Des. 2009, 23, 491-500.
25. Ngan, C.; Beglov, D.; Rudnitskaya, A. N.; Kozakov, D.; Waxman, D. J.; Vajda, S. The structural basis of pregnane X receptor binding promiscuity. Biochemistry 2009, 48, 11572-11581.
26. Kozakov, D.; Hall, D. R.; Chuang, G.; Cencic, R.; Brenke, R.; Grove, L. E.; Beglov, D.; Pelletier, J.; Whitty, A.; Vajda, S. Structural conservation of protein hot spots in protein-protein interfaces. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 13528-13533.
27. Congreve, M.; Aharony, D.; Albert, J.; Callaghan, O.; Campbell, J.; Carr, R. A.; Chessari, G.; Cowan, S.; Edwards, P. D.; Frederickson, M.; McMenamin, R.; Murray, C. W.; Patel, S.; Wallis, N. Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase. J. Med. Chem. 2007, 50, 1124-1132. (Pubitemid 46496313)
28. Fedorov, R.; Hartmann, E.; Ghosh, D. K.; Schlichting, I. Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms. J. Biol. Chem. 2003, 278, 45818-45825. (Pubitemid 37432727)
29. Griffin, R. J.; Henderson, A.; Curtin, N. J.; Echalier, A.; Endicott, J. A.; Hardcastle, I. R.; Newell, D. R.; Noble, M. E. M.; Wang, L.; Golding, B. T. Searching for Cyclin-Dependent Kinase Inhibitors Using a New Variant of the Cope Elimination. J. Am. Chem. Soc. 2006, 128, 6012-6013.
30. Katz, B. A.; Sprengeler, P. A.; Luong, C.; Verner, E.; Elrod, K.; Kirtley, M.; Janc, J.; Spencer, J. R.; Breitenbucher, J. G.; Hui, H.; McGee, D.; Allen, D.; Martelli, A.; Mackman, R. L. Engineering inhibitors highly selective for the S1 sites of SER190 trypsin-like serine protease drug targets. Chem. Biol. 2001, 8, 1107-1121. (Pubitemid 33119187)
31. Marino, J. P. Jr.; Fisher, P. W.; Hofmann, G. A.; Kirkpatrick, R. B.; Janson, C. A.; Johnson, R. K.; Ma, C.; Mattern, M.; Meek, T. D.; Ryan, M. D.; Schulz, C.; Smith, W. W.; Tew, D. G.; Tomazek, T. A. Jr.; Veber, D. F.; Xiong, W. C.; Yamamoto, Y.; Yamashita, K.; Yang, G.; Thompson, S. K. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J. Med. Chem. 2007, 50, 3777-3785. (Pubitemid 47292041)
32. Ritschel, T.; Hoertner, S.; Heine, A.; Diederich, F.; Klebe, G. Crystal structure analysis and in silico pKa calculations suggest strong pKa shifts of ligands as driving force for high-affinity binding to TGT. ChemBioChem 2009, 10, 716-727.
33. Ritschel, T.; Kohler, P. C.; Neudert, G.; Heine, A.; Diederich, F.; Klebe, G. How to replace the residual solvation shell of polar active site residues to achieve nanomolar inhibition of tRNA-guanine transglycosylase. ChemMedChem 2009, 4, 2012-2023.
34. Selinsky, B. S.; Gupta, K.; Sharkey, C. T.; Loll, P. J. Structural analysis of NSAID binding by prostaglandin H2 synthase: Timedependent and time-independent inhibitors elicit identical enzyme conformations. Biochemistry 2001, 40, 5172-5180. (Pubitemid 32373999)
35. Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper, B.; Park, Y.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J. K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. 2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)- N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: A Selective a-Amino Amide Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes. J. Med. Chem. 2006, 49, 3614-3627. (Pubitemid 43902466)
36. Hiramatsu, H.; Kyono, K.; Higashiyama, Y.; Fukushima, C.; Shima, H.; Sugiyama, S.; Inaka, K.; Yamamoto, A.; Shimizu, R. The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed beta-propeller fold. Biochem. Biophys. Res. Commun. 2003, 302, 849-854. (Pubitemid 36294052)
37. Rasmussen, H. B.; Branner, S.; Wiberg, F. C.; Wagtmann, N. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 2003, 10, 19-25. (Pubitemid 36034172)
38. Howard, N.; Abell, C.; Blakemore, W.; Chessari, G.; Congreve, M.; Howard, S.; Jhoti, J.; Murray, C. W.; Seavers, L. C. A.; Van Montfort, R. L. M. Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. J. Med. Chem. 2006, 59, 1346-1355. (Pubitemid 43271886)
39. Qiu, X.; Yin, M.; Padmanabhan, K. P.; Krstenansky, J. L.; Tulinsky, A. Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor. J. Biol. Chem. 1993, 268, 20318-20326. (Pubitemid 23278939)
40. Huth, J. R.; Park, C.; Petros, A. M.; Kunzer, A. R.; Wendt, M. D.; Wang, X.; Lynch, C. L.; Mack, J. C.; Swift, K. M.; Judge, R. A.; Chen, J.; Richardson, P. L.; Jin, S.; Tahir, S. K.; Matayoshi, E. D.; Dorwin, S. A.; Ladror, U. S.; Severin, J. M.; Walter, K. A.; Bartley, D. M.; Fesik, S. W.; Elmore, S. W.; Hajduk, P. J. Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies. Chem. Biol. Drug Des. 2007, 70, 1-12. (Pubitemid 47057425)
41. Dymock, B. W.; Barril, X.; Brough, P. A.; Cansfield, J. E.; Massey, A.; McDonald, E.; Hubbard, R. E.; Roughley, S. D.; Webb, P.; Workman, P.; Wright, L.; Drysdale, M. J. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J. Med. Chem. 2005, 48, 4212-5. (Pubitemid 40884922)
42. Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell 1997, 89, 239-250. (Pubitemid 27199896)
43. Brough, P. A.; Aherne, W.; Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J. E.; Cheung, K.-M. J.; Collins, I.; Davies, N. G. M.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.; Finch, H.; Fink, A.; Hayes, A.; Howes, R.; Hubbard, R. E.; James, K.; Jordan, A. M.; Lockie, A.; Martins, V.; Massey, A.; Matthews, T. P.; McDonald, E.; Northfield, C. J.; Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.; Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.; Workman, P. Wright, L.4,5-Diarylisoxazole HSP90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer. J. Med. Chem. 2008, 51, 196-218.
44. Hajduk, P. J.; Boyd, S.; Nettesheim, D.; Nienaber, V.; Severin, J.; Smith, R.; Davidson, D.; Rockway, T.; Fesik, S. W. Identification of novel inhibitors of urokinase via NMR-based screening. J. Med. Chem. 2000, 43, 3862-3866.
45. Jiang, L.-G.; Yu, H.-Y.; Yuan, C.; Wang, J.-D.; Chen, L.-Q.; Meehan, E. J.; Huang, Z.-X.; Huang, M.-D. Crystal structures of 2-aminobenzothiazole-based inhibitors in complexes with urokinase-type plasminogen activator. Chin. J. Struct. Chem. 2009, 28, 1427-1432.
46. Hartshorn, M. J.; Murray, C. W.; Cleasby, A.; Frederickson, M.; Tickle, I. J.; Jhoti, H. Fragment-based lead discovery using X-ray crystallography. J. Med. Chem. 2005, 48, 403-413. (Pubitemid 40139783)
47. Davies, T. G.; Bentley, J.; Arris, C. E.; Boyle, F. T.; Curtin, N. J.; Endicott, J. A.; Gibson, A. E.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Jewsbury, P.; Johnson, L. N.; Mesguiche, V.; Newell, D. R.; Noble, M. E.; Tucker, J. A.; Wang, L.; Whitfield, H. J. Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor. Nat. Struct. Biol. 2002, 9, 745-749.
48. Schulze-Gahmen, U.; Brandsen, J.; Jones, H. D.; Morgan, D. O.; Meijer, L.; Vesely, J.; Kim, S. H. Multiple modes of ligand recognition: Crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins 1995, 22, 378-391.
49. Romier, C.; Reuter, K; Suck, D.; Ficner, R. Crystal structure of tRNA-guanine transglycosylase: RNA modification by base exchange. EMBO J. 1996, 15, 2850-2857. (Pubitemid 26176263)
50. Meyer, E. A.; Furler, M.; Diederich, F.; Brenk, R.; Klebe, G. Synthesis and In Vitro Evaluation of 2-Aminoquinazolin-4(3H)-one-Based Inhibitors for tRNA-Guanine Transglycosylase (TGT). Helv. Chim. Acta 2004, 87, 1333-1356. (Pubitemid 38924109)
51. Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.; Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C. K.; Smith, W. W.; Janson, C. A.; Ryan, M. D.; Zhang, G. F.; Johanson, K. O.; Kirkpatrick, R. B.; Ho, T. F.; Fisher, P. W.; Mattern, M. R.; Johnson, R. K.; Hansbury, M. J.; Winkler, J. D.; Ward, K. W.; Veber, D. F.; Thompson, S. K. 4-Aryl-1,2,3-triazole: A novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. J. Med. Chem. 2005, 48, 5644-5647. (Pubitemid 41298336)
52. Liu, S.; Widom, J.; Kemp, C. W.; Crews, C. M.; Clardy, J. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 1998, 282, 1324-1327. (Pubitemid 28524496)
53. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J. Apo and inhibitor complex structures of BACE (beta-secretase). J. Mol. Biol. 2004, 343, 407-416. (Pubitemid 39296874)
54. Matter, H.; Kumar, H. S.; Fedorov, R.; Frey, A.; Kotsonis, P.; Hartmann, E.; Fröhlich, L. G.; Reif, A.; Pfleiderer, W.; Scheurer, P.; Ghosh, D. K.; Schlichting, I.; Schmidt, H. H. Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. J. Med. Chem. 2005, 48, 4783-4792. (Pubitemid 41033121)
55. Picot, D.; Loll, P. J.; Garavito, R. M. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994, 367, 243-249. (Pubitemid 24051139)
56. Chen, Y.; Shoichet, B. K. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat. Chem. Biol. 2009, 5, 358-364.
57. Haider, M. K.; Bertrand, H. O.; Hubbard, R. E. Predicting fragment binding poses using a combined MCSS MM-GBSA approach. J. Chem. Inf. Model. 2011, 51, 1092-1105.
58. Verdonk, M. L.; Giangreco, I.; Hall, R. J.; Korb, O.; Mortenson, P. N.; Murray, C. W. Docking performance of fragments and druglike compounds. J. Med. Chem. 2011, 54, 5422-5431.
59. Reynolds, C. H.; Bembenek, S. D.; Tounge, B. A. The role of molecular size in ligand efficiency. Bioorg. Med. Chem. Lett. 2007, 17, 4258-4261. (Pubitemid 47028600)
60. Reynolds, C. H.; Bembenek, S. D.; Tounge, B. A. Ligand binding efficiency: Trends, physical basis, and implications. J. Med. Chem. 2008, 51, 2432-2438. (Pubitemid 351628504)
61. Gilson, M. K.; Sharp, K. A.; Honig, B. A. Calculating the electrostatic potential of molecules in solution: Method and error assessment. J. Comput. Chem. 1988, 9, 327-335.
62. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 1983, 4, 187-217.
63. Schaefer, M.; Karplus, M. A. A comprehensive analytical treatment of continuum electrostatics. J. Phys. Chem. 1996, 100, 1578-1599. (Pubitemid 126789971)