A minimalist approach to fragment-based ligand design using common rings and linkers: Application to kinase inhibitors

Proteins: Structure, Function and Genetics

Volumn 57, Issue 1, 2004, Pages 36-50

  Aronov, Alex M ^a   Bemis, Guy W ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

Constrained docking; Fragment based ligand design; Kinase inhibitors; Modular scaffold assembly; Virtual library screening

Indexed keywords

ABELSON KINASE; BCR ABL PROTEIN; CYCLIN DEPENDENT KINASE 2; CYCLOOXYGENASE 2; ENZYME INHIBITOR; LIGAND; PHOSPHOTRANSFERASE INHIBITOR;

ANALYTIC METHOD; ARTICLE; DNA LIBRARY; ENZYME ANALYSIS; ENZYME INHIBITION; ENZYME INHIBITOR COMPLEX; HIGH THROUGHPUT SCREENING; LIGAND BINDING; MACROMOLECULE; MULTIGENE FAMILY; PRIORITY JOURNAL; PROTEIN ASSEMBLY; PROTEIN MOTIF; STRUCTURE ANALYSIS;

ALGORITHMS; BINDING SITES; CDC2-CDC28 KINASES; COMBINATORIAL CHEMISTRY TECHNIQUES; COMPUTER SIMULATION; CYCLIN-DEPENDENT KINASE 2; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; DRUG DESIGN; ISOENZYMES; LIGANDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PIPERAZINES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PYRIMIDINES; SRC-FAMILY KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4444262413     PISSN: 08873585     EISSN: None     Source Type: Journal    
DOI: 10.1002/prot.20173     Document Type: Article

References (75)

1. Golebiowski A, Klopfenstein SR, Portlock DE. Lead compounds discovered from libraries. Curr Opin Chem Biol 2001;5:273-284.
2. Boehm HJ, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W, Kostrewa D, Kuehne H, Luebbers T, Meunier-Keller N, Mueller F. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization: a promising alternative to random screening. J Med Chem 2000;43:2664-2674.
3. Walters WP, Stahl MT, Murcko MA. Virtual screening- an overview. Drug Discov Today 1998;3:160-178.
4. Mason JS, Good AC, Martin EJ. 3-D pharmacophores in drug discovery. Curr Pharm Des 2001;7:567-597.
5. Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr Opin Chem Biol 2002;6:439-446.
6. Kuntz ID. Structure-based strategies for drug design and discovery. Science 1992;257:1078-1082.
7. Fejzo J, Lepre CA, Peng JW, Bemis GW, Ajay, Murcko MA, Moore JM. The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. Chem Biol 1999;6:755-769.
8. Fejzo J, Lepre C, Xie X. Application of NMR screening in drug discovery. Curr Top Med Chem 2003;3:81-97.
9. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science 1996;274:1531-1534.
10. Hajduk PJ, Gomtsyan A, Didomenico S, Cowart M, Bayburt EK, Solomon L, Severin J, Smith R, Walter K, Holzman TF, Stewart A, McGaraughty S, Jarvis MF, Kowaluk EA, Fesik SW. Design of adenosine kinase inhibitors from the NMR-based screening of fragments. J Med Chem 2000;43:4781-4786.
11. Szczepankiewicz BG, Liu G, Hajduk PJ, Abad-Zapatero C, Pei Z, Xin Z, Lubben TH, Trevillyan JM, Stashko MA, Ballaron SJ, Liang H, Huang F, Hutchins CW, Fesik SW, Jirousek MR. Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J Am Chem Soc 2003;125:4087-4096.
12. Jahnke W, Perez LB, Paris CG, Strauss A, Fendrich G, Nalin CM. Second-site NMR screening with a spin-labeled first ligand. J Am Chem Soc 2000;122:7394-7395.
13. Blundell TL, Jhoti H, Abell C. High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 2002;1:45-54.
14. Buchanan SG. Structural genomics: bridging functional genomics and structure-based drug design. Curr Opin Drug Discov Devel 2002;5:367-381.
15. Nienaber VL, Richardson PL, Klighofer V, Bouska JJ, Giranda VL, Greer J. Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol 2000;18:1105-1108.
16. Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA. Site-directed ligand discovery. Proc Natl Acad Sci USA 2000;97:9367-9372.
17. Braisted AC, Oslob JD, Delano WL, Hyde J, McDowell RS, Waal N, Yu C, Arkin MR, Raimundo BC. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J Am Chem Soc 2003;125:3714-3715.
18. Egan WJ, Walters WP, Murcko MA. Guiding molecules towards drug-likeness. Curr Opin Drug Discov Devel 2002;5:540-549.
19. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997;23:3-25.
20. Bemis GW, Murcko MA. The properties of known drugs. 1. Molecular frameworks. J Med Chem 1996;39:2887-2893.
21. Bemis GW, Murcko MA. Properties of known drugs: 2. Side chains. J Med Chem 1999;42:5095-5099.
22. Ajay, Walters WP, Murcko MA. Can we learn to distinguish between "drug-like" and "nondrug-like" molecules? J Med Chem 1998;41:3314-3324.
23. McGovern SL, Caselli E, Grigorieff N, Shoichet BK. A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 2002;45:1712-1722.
24. Teague SJ, Davis AM, Leeson PD, Oprea T. The design of leadlike combinatorial libraries. Angew Chem Int Ed Engl 1999;38:3743-3748.
25. Oprea TI, Davis AM, Teague SJ, Leeson PD. Is there a difference between leads and drugs?: a historical perspective. J Chem Inf Comput Sci 2001;41:1308-1315.
26. Hann MM, Leach AR, Harper G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comput Sci 2001;41:856-864.
27. Schneider G. Trends in virtual combinatorial library design. Curr Med Chem 2002;9:2095-2101.
28. Goodford PJ. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 1985;28:849-857.
29. Miranker A, Karplus M. Functionality maps of binding sites: a multiple copy simultaneous search method. Proteins 1991;11:29-34.
30. Eisen MB, Wiley DC, Karplus M, Hubbard RE. HOOK: a program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site. Proteins 1994;19:199-221.
31. Lauri G, Bartlett PA. CAVEAT: a program to facilitate the design of organic molecules. J Comput Aided Mol Des 1994;8:51-66.
32. Bohacek RS, McMartin C. Multiple highly diverse structures complementary to enzyme binding sites- results of extensive application of a de novo design method incorporating combinatorial growth. J Am Chem Soc 1994;116:5560-5571.
33. Nishibata Y, Itai A. Confirmation of usefulness of a structure construction program based on three-dimensional receptor structure for rational lead generation. J Med Chem 1993;36:2921-2928.
34. Rotstein SH, Murcko MA. GroupBuild: a fragment-based method for de novo drug design. J Med Chem 1993;36:1700-1710.
35. Moon JB, Howe WJ. Computer design of bioactive molecules: a method for receptor-based de novo ligand design. Proteins 1991;11:314-328.
36. DeWitte RS, Shakhnovich EI. SMoG: de novo design method based on simple, fast, and accurate free energy estimates: 1. Methodology and supporting evidence. J Am Chem Soc 1996;118:11733-11744.
37. Liu H, Duan Z, Luo Q, Shi Y. Structure-based ligand design by dynamically assembling molecular building blocks at binding site. Proteins 1999;36:462-470.
38. Zhu J, Yu H, Fan H, Liu H, Shi Y. Design of new selective inhibitors of cyclooxygenase-2 by dynamic assembly of molecular building blocks. J Comput Aided Mol Des 2001;15:447-463.
39. Pegg SC, Haresco JJ, Kuntz ID. A genetic algorithm for structure-based de novo design. J Comput Aided Mol Des 2001;15:911-933.
40. Sheridan RP, SanFeliciano SG, Kearsley SK. Designing targeted libraries with genetic algorithms. J Mol Graph Model 2000;18:320-334, 525.
41. Schneider G, Clement-Chomienne O, Hilfiger L, Schneider P, Kirsch S, Bohm HJ, Neidhart W. Virtual screening for bioactive molecules by evolutionary de novo design. Angew Chem Int Ed Engl 2000;39:4130-4133.
42. Schneider G, Lee ML, Stahl M, Schneider P. De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks. J Comput Aided Mol Des 2000;14:487-494.
43. Honma T, Hayashi K, Aoyama T, Hashimoto N, Machida T, Fukasawa K, Iwama T, Ikeura C, Ikuta M, Suzuki-Takahashi I, Iwasawa Y, Hayama T, Nishimura S, Morishima H. Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J Med Chem 2001;44:4615-4627.
44. Lewell XQ, Judd DB, Watson SP, Hann MM. RECAP-retrosynthetic combinatorial analysis procedure: a powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry. J Chem Inf Comput Sci 1998;38:511-522.
45. Stahl M, Todorov NP, James T, Mauser H, Boehm HJ, Dean PM. A validation study on the practical use of automated de novo design. J Comput Aided Mol Des 2002;16:459-478.
46. World Drug Index, London, UK: Derwent Information; 1996.
47. Comprehensive Medicinal Chemistry (CMC-3D). San Leandro, CA: MDL Information Systems Inc.; 1996.
48. Dumas J. Protein kinase inhibitors: emerging pharmacophores 1997-2000. Exp Opin Ther Pat 2001;11:405-429.
49. CORINA. Version 2.61. Erlangen, Germany: Molecular Networks GmbH; 2001.
50. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000;289:1938-1942.
51. Cheetham GM, Knegtel RM, Coll JT, Renwick SB, Swenson L, Weber P, Lippke JA, Austen DA. Crystal structure of Aurora-2, an oncogenic serine/threonine kinase. J Biol Chem 2002;277:42419-42422.
52. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 1998;281:533-538.
53. Wang Z, Canagarajah BJ, Boehm JC, Kassisa S, Cobb MH, Young PR, Abdel-Meguid S, Adams JL, Goldsmith EJ. Structural basis of inhibitor selectivity in MAP kinases. Structure 1998;6:1117-1128.
54. ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol 2001;8:593-596.
55. Bossemeyer D, Engh RA, Kinzel V, Ponstingl H, Huber R. Phosphotransferase and substrate binding mechanism of the cAMP-dependent protein kinase catalytic subunit from porcine heart as deduced from the 2.0 A structure of the complex with Mn2+ adenylyl imidodiphosphate and inhibitor peptide PKI(5-24). EMBO J 1993;12:849-859.
56. Xu W, Doshi A, Lei M, Eck MJ, Harrison SC. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell 1999;3:629-638.
57. Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP. 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 1997;11:425-445.
58. Murray CW, Auton TR, Eldridge MD. Empirical scoring functions: II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model. J Comput Aided Mol Des 1998;12:503-519.
59. Stover DR, Lydon NB, Nunes JJ. Recent advances in protein kinase inhibition: current molecular scaffolds used for inhibitor synthesis. Curr Opin Drug Discov Devel 1999;2:274-285.
60. Shewchuk L, Hassell A, Wisely B, Rocque W, Holmes W, Veal J, Kuyper LF. Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase. J Med Chem 2000;43:133-138.
61. Wang YD, Miller K, Boschelli DH, Ye F, Wu B, Floyd MB, Powell DW, Wissner A, Weber JM, Boschelli F. Inhibitors of src tyrosine kinase: the preparation and structure-activity relationship of 4-anilino-3-cyanoquinolines and 4-anilinoquinazolines. Bioorg Med Chem Lett 2000;10:2477-2480.
62. Halgren TA. MMFF VI: MMFF94s option for energy minimization studies. J Comput Chem 1999;20:720-729.
63. Molecular Operating Environment (MOE). 2002.03. Montreal, Canada: Chemical Computing Group Inc.; 2002.
64. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 1996;384:644-648.
65. Fabiola GF, Pattabhi V, Nagarajan K. Structural basis for selective inhibition of COX-2 by nimesulide. Bioorg Med Chem 1998;6:2337-2344.
66. Garcia-Nieto R, Perez C, Checa A, Gago F. Molecular model of the interaction between nimesulide and human cyclooxygenase-2. Rheumatology (Oxford) 1999;38(Suppl 1):14-18.
67. Chapman KB, Szostak JW. In vitro selection of catalytic RNAs. Curr Opin Struct Biol 1994;4:618-622.
68. Sen D, Geyer CR. DNA enzymes. Curr Opin Chem Biol 1998;2:680-687.
69. Taylor SV, Walter KU, Kast P, Hilvert D. Searching sequence space for protein catalysts. Proc Natl Acad Sci USA 2001;98:10596-10601.
70. Stout TJ, Sage CR, Stroud RM. The additivity of substrate fragments in enzyme-ligand binding. Structure 1998;6:839-848.
71. Pierce AC, Sandretto KL, Bemis GW. Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding. Proteins 2002;49:567-576.
72. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble ME, Sausville EA, Schultz R, Yu W. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 2000;43:2797-2804.
73. Davies TG, Bentley J, Arris CE, Boyle FT, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Hardcastle IR, Jewsbury P, Johnson LN, Mesguiche V, Newell DR, Noble ME, Tucker JA, Wang L, Whitfield HJ. Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor. Nat Struct Biol 2002;9:745-749.
74. Mavunkel BJ, Chakravarty S, Perumattam JJ, Luedtke GR, Liang X, Lim D, Xu Y, Laney M, Liu DY, Schreiner GF, Lewicki JA, Dugar S. Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue. Bioorg Med Chem Lett 2003;13:3087-3090.
75. Guo Q, Wang LH, Ruan KH, Kulmacz RJ. Role of Va1509 in time-dependent inhibition of human prostaglandin H synthase-2 cyclooxygenase activity by isoform-selective agents. J Biol Chem 1996;271:19134-19139.