Drugs, their targets and the nature and number of drug targets

Nature Reviews Drug Discovery volume 5, pages821–834(2006)Cite this article

A Corrigendum to this article was published on 01 February 2007

Abstract

What is a drug target? And how many such targets are there? Here, we consider the nature of drug targets, and by classifying known drug substances on the basis of the discussed principles we provide an estimation of the total number of current drug targets.

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References

  1. 1

    Drews, J. & Ryser, S. The role of innovation in drug development. Nature Biotechnol. 15, 1318–1319 (1997).

    Article  CAS  Google Scholar 

  2. 2

    Burgess, J. & Golden, J. Cracking the druggable genome. Bio-IT World, [online] (2002).

    Google Scholar 

  3. 3

    Hopkins, A. & Groom, C. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).

    Article  CAS  Google Scholar 

  4. 4

    Saunders, J. G-protein-coupled receptors in drug discovery. Bioorg. Med. Chem. Lett. 15, 3653 (2005)

    Article  CAS  Google Scholar 

  5. 5

    Zambrowicz, B. P. & Sands. A. T. Knockouts model the 100 best-selling drugs — will they model the next 100? Nature Rev. Drug Discov. 2, 38–51 (2003).

    Article  CAS  Google Scholar 

  6. 6

    Jonker, D. M., Visser, S. A. G., van der Graaf, P. H., Voskuyl, R. A. & Danhof, M. Towards a mechanism-based analysis of pharmacodynamic drug–drug interactions in vivo. Pharmacol. Therapeut. 106, 1–18 (2005).

    Article  CAS  Google Scholar 

  7. 7

    Agnati, L. F., Fuxe, K. & Ferré, S. How receptor mosaics decode transmitter signals. Possible relevance of cooperativity. Trends Biochem. Sci. 30, 188–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Heien, M. L. A. V. et al. Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats. Proc. Natl Acad. Sci. USA 102, 10023–10028 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Mitcheson, J. S., Chen, J. & Sanguinetti, M. C. Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J. Gen. Physiol. 115, 229–240 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hyman, S. E. & Fenton, W. S. What are the right targets for psychopharmacology? Science 299, 350–351 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Apic, G., Ignjatovic, T., Boyer, S. & Russell, R. B. Illuminating drug discovery with biological pathways. FEBS Lett. 579, 1872–1877 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Schneider, G. Trends in virtual combinatorial library design. Curr. Med. Chem. 9, 2095–2101 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Goodnow, R. A. Jr., Guba, W. & Haap, W. Library design practices for success in lead generation with small molecule libraries. Comb. Chem. High Throughput Screen. 6, 649–660 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Hendlich, M., Bergner, A., Gunther, J. & Klebe, G. Relibase: design and development of a database for comprehensive analysis of protein-ligand interactions. J. Mol. Biol. 326, 607–620 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Gohlke, H. & Klebe, G. Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Angew. Chem. Int. Ed. Engl. 41, 2644–2676 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Schwabe, U. ATC-Code (Wissenschaftliches Institut der AOK, Bonn, Germany, 1995).

    Google Scholar 

  17. 17

    Imming, P. et al. A classification of drug substances according to their mechanism of action. Pharmazie 59, 579–589 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Swinney, D. C. Biochemical mechanisms of drug action: what does it take for success? Nature Rev. Drug Discov. 3, 801–808 (2004).

    Article  CAS  Google Scholar 

  19. 19

    World Health Organization. The Essential Medicines List, [online] (2002).

  20. 20

    Approved Drug Products 25th edition and Cumulative Supplement (US Department of Health and Human Services, 2005).

  21. 21

    Pharmazeutische Zeitung Neue Arzneistoffe, [online], (2005).

  22. 22

    CDER Drug and Biologic Approval Reports [online], (2006).

  23. 23

    Robertson, J. G. Mechanistic basis of enzyme-targeted drugs. Biochemistry 44, 5561–5571 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Alexander, S. P. H, Mathie, A. & Peters, J. A. TiPS nomenclature supplement. Trends Pharmacol. Sci. 12, 1–146 (2001).

    Article  Google Scholar 

  25. 25

    Mutschler, E., Geisslinger, G., Kroemer, H. K., Schä fer-Korting, M. Mutschler Arzneimittelwirkungen (Wissenschaftliche, Stuttgart, 2001).

    Google Scholar 

  26. 26

    Goldberg, N. R. et al. A. Probing conformational changes in neurotransmitter transporters: a structural context. Eur. J. Pharmacol. 479, 3–12 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Saier Jr., M. H. A functional-phylogenetic system for the classification of transport proteins. J. Cell Biochem. Suppl. 32–33, 84–94 (1999).

    Article  Google Scholar 

  28. 28

    Krishnan, K., Campbell, S., Abdel-Rahman, F., Whaley, S. & Stone, W. L. Cancer chemoprevention drug targets. Curr. Drug Targets 4, 45–54 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Morphy, R. & Rankovic, Z. Designed multiple ligands: an emerging drug discovery paradigm. J. Med. Chem. 48, 6523–6543 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Rev. Drug Discov. 3, 353–359 (2004).

    Article  CAS  Google Scholar 

  31. 31

    Law, M. R., Wald, J., Morris, J. K. & Jordan, R. E. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Br. Med. J. 326, 1427–1431 (2003).

    Article  CAS  Google Scholar 

  32. 32

    Keith, C. T., Borisy, A. A. & Stockwell, B. R. Multicomponent therapeutics for networked systems. Nature Rev. Drug Discov. 4, 1–7 (2005).

    Article  CAS  Google Scholar 

  33. 33

    Roden, D. M. Antiarrhythmic drugs: past, present, and future. J. Cardiovasc. Electrophysiol. 14, 1389–1396 (2003).

    Article  Google Scholar 

  34. 34

    Grosser, T., Fries, S. & FitzGerald, G. A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4–15 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Sozzani, S. et al. Propranolol, a phosphatidate phosphohydrolase inhibitor, also inhibits protein kinase C. J. Biol. Chem. 267, 20481–20488 (1992).

    CAS  PubMed  Google Scholar 

  36. 36

    Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. & Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625–1630 (2005).

    Article  CAS  Google Scholar 

  37. 37

    Chulia, S. et al. Relationships between structure and vascular activity in a series of benzylisoquinolines. Br. J. Pharmacol. 122, 409–416 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Frantz, S. Playing dirty. Nature 437, 942–943 (2005).

    Article  CAS  Google Scholar 

  39. 39

    Petersen, E. N. The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr. Scand. Suppl. 369, 7–13 (1992).

    Article  CAS  Google Scholar 

  40. 40

    Baker, G. B., Coutts, R. T., McKenna, K. F. & Sherry-McKenna, R. L. Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review. J. Psychiatry Neurosci. 17, 206–214 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Haefely, W. et al. Pharmacology of moclobemide. Clin. Neuropharmacol. 16 (Suppl 2), 8–18 (1993).

    Google Scholar 

  42. 42

    Garavito, R. M., Malkowski, M. G. & DeWitt, D. L. The structures of prostaglandin endoperoxide H synthases-1 and -2. Prostaglandins Other Lipid Mediat. 68–69, 129–152 (2002).

    Article  Google Scholar 

  43. 43

    Smith, W. L. & Song, I. The enzymology of prostaglandin endoperoxide H synthases-1 and-2. Prostaglandins Other Lipid Mediat. 68–69, 115–28 (2002).

    Article  Google Scholar 

  44. 44

    Hogestatt, E. D. et al. Conversion of acetaminophen to the bioactive N-acyl phenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J. Biol. Chem. 280, 31405–31412 (2005).

    Article  CAS  Google Scholar 

  45. 45

    Mann, K. G. The challenge of regulating anticoagulant drugs: Focus on warfarin. Am. Heart J. 149 (Suppl 1), 36–42 (2005).

    Article  CAS  Google Scholar 

  46. 46

    Miller, R. W. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin. Oncol. 30 (4 Suppl 14), 3–11 (2003).

    Article  CAS  Google Scholar 

  47. 47

    Maertens, J. A. History of the development of azole derivatives. Clin. Microbiol. Infect. 10 (Suppl 1), 1–10 (2004).

    Article  CAS  Google Scholar 

  48. 48

    Klotz, U. The role of aminosalicylates at the beginning of the new millennium in the treatment of chronic inflammatory bowel disease. Eur. J. Clin. Pharmacol. 56, 353–362 (2000).

    Article  CAS  Google Scholar 

  49. 49

    Parnes, S. M. The role of leukotriene inhibitors in patients with paranasal sinus disease. Curr. Opin. Otolaryngol. Head Neck. Surg. 11, 184–191 (2003).

    Article  Google Scholar 

  50. 50

    Cooper, D. S. Antithyroid drugs. N. Engl. J. Med. 352, 905–917 (2005).

    CAS  Google Scholar 

  51. 51

    Allison, A. C. & Eugui, E. M. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47, 85–118 (2000).

    Article  CAS  Google Scholar 

  52. 52

    Stancu, C. & Sima, A. Statins: mechanism of action and effects. J. Cell. Mol. Med. 5, 378–387 (2001).

    Article  CAS  Google Scholar 

  53. 53

    Bull, H. G. et al. Mechanism-based inhibition of human steroid 5a-reductase by finasteride: enzyme-catalyzed formation of NADP-Dihydrofinasteride, a potent bisubstrate analog inhibitor. J. Am. Chem. Soc. 118, 2359–2365 (1996).

    Article  CAS  Google Scholar 

  54. 54

    Matthews, D. A. et al. Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim. J. Biol. Chem. 260, 381–391 (1985).

    CAS  PubMed  Google Scholar 

  55. 55

    Goldman, I. D. & Zhao, R. Molecular, biochemical, and cellular pharmacology of pemetrexed. Semin. Oncol. 29 (6 Suppl 18), 3–17 (2002).

    Article  Google Scholar 

  56. 56

    Anderson, A. C. Targeting DHFR in parasitic protozoa. Drug Discov. Today 10, 121–128 (2005).

    Article  CAS  Google Scholar 

  57. 57

    Fox, R. I. Mechanism of action of leflunomide in rheumatoid arthritis. J. Rheumatol. Suppl. 53, 20–26 (1998).

    CAS  PubMed  Google Scholar 

  58. 58

    Heath, R. J., White, S. W. & Rock, C. O. Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl. Microbiol. Biotechnol. 58, 695–703 (2002).

    Article  CAS  Google Scholar 

  59. 59

    Ryder, N. S. The mechanism of action of terbinafine. Clin. Exp. Dermatol. 14, 98–100 (1989).

    Article  CAS  Google Scholar 

  60. 60

    Barrett-Bee, K. & Dixon, G. Ergosterol biosynthesis inhibition: a target for antifungal agents. Acta Biochim. Pol. 42, 465–479 (1995).

    CAS  PubMed  Google Scholar 

  61. 61

    Borges, F., Fernandes, E. & Roleira, F. Progress towards the discovery of xanthine oxidase inhibitors. Curr. Med. Chem. 9, 195–217 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Brownlee, J. M., Johnson-Winters, K., Harrison, D. H. & Moran, G. R. Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC. Biochemistry 43, 6370–6377 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Yarbro, J. W. Mechanism of action of hydroxyurea. Semin. Oncol. 19 (Suppl 9), 1–10 (1992).

    CAS  PubMed  Google Scholar 

  64. 64

    Hofmann, J. Modulation of protein kinase C in antitumor treatment. Rev. Physiol. Biochem. Pharmacol. 142, 1–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Jendrossek, V. & Handrick, R. Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers. Curr. Med. Chem. Anti-Canc. Agents 3, 343–353 (2003).

    Article  CAS  Google Scholar 

  66. 66

    Atkins, M., Jones, C. A. & Kirkpatrick, P. Sunitinib maleate. Nature Rev. Drug Discov. 5, 279–280 (2006).

    Article  CAS  Google Scholar 

  67. 67

    Schlünzen, F. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413, 814–821 (2001).

    Article  Google Scholar 

  68. 68

    Mannisto, P. T. et al. Characteristics of catechol O-methyl-transferase (COMT) and properties of selective COMT inhibitors. Prog. Drug Res. 39, 291–350 (1992).

    CAS  PubMed  Google Scholar 

  69. 69

    Komo, K., Oizumi, K. & Oka, S. Mode of action of rifampin on mycobacteria. Am. Rev. Respir. Dis. 107, 1006–1012 (1973).

    Google Scholar 

  70. 70

    Painter, G. R., Almond, M. R., Mao, S. & Liotta, D. C. Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase. Curr. Top. Med. Chem. 4, 1035–1044 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Zapor, M. J., Cozza, K. L., Wynn, G. H., Wortmann, G. W. & Armstrong, S. C. Antiretrovirals, Part II: focus on non-protease inhibitor antiretrovirals (NRTIs, NNRTIs, and fusion inhibitors). Psychosomatics 45, 524–535 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Bell, C., Matthews, G. V. & Nelson, M. R. Non-nucleoside reverse transcriptase inhibitors — an overview. Int. J. STD AIDS 14, 71–77 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Young, S. D. et al. L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 39, 2602–2605 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Earnshaw, D. L., Bacon, T. H., Darlison, S. J., Edmonds, K., Perkins, R. M. & Vere Hodge, R. A. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob. Agents Chemother. 36, 2747–2757 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Walther, M. M., Trahan, E. E., Cooper, M., Venzon, D. & Linehan, W. M. Suramin inhibits proliferation and DNA synthesis in transitional carcinoma cell lines. J. Urol. 152, 1599–1602 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Gurvich, N., Tsygankova, O. M., Meinkoth, J. L. & Klein, P. S. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res. 64, 1079–1086 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Angehagen, M., Ben-Menachem, E., Ronnback, L. & Hansson, E. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem. Res. 28, 333–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Buchdunger, E. et al. ABL protein-tyrosine kinase inhibitor STI571 Inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 295, 139–145 (2000).

    CAS  Google Scholar 

  79. 79

    Minna, J. D. & Dowell, J. Erlotinib hydrochloride. Nature Rev. Drug Discov. 4, S14–S15 (2005).

    Article  Google Scholar 

  80. 80

    Yoon, H. J. et al. Crystallization and preliminary X-ray crystallographic analysis of UDP-N-acetylglucosamine enolpyruvyl transferase from Haemophilus influenzae in complex with UDP-N-acetylglucosamine and fosfomycin. Mol. Cell 19, 398–401 (2005).

    CAS  Google Scholar 

  81. 81

    El Zoeiby, A., Sanschagrin, F. & Levesque, R. C. Structure and function of the Mur enzymes: development of novel inhibitors. Mol. Microbiol. 47, 1–12 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Goto, M. et al. M. Structural determinants for branched-chain aminotransferase isozyme specific inhibition by the anticonvulsant drug gabapentin. J. Biol. Chem. 280, 37246–37256 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Adams, J. The proteasome: a suitable antineoplastic target. Nature Rev. Cancer 4, 349–360 (2004).

    Article  CAS  Google Scholar 

  84. 84

    Sugimoto, H., Ogura, H., Arai, Y., Limura, Y. & Yamanishi, Y. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn. J. Pharmacol. 89, 7–20 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Kwong, T. C. Organophosphate pesticides: biochemistry and clinical toxicology. Ther. Drug Monit. 24, 144–149 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Fisone, G., Borgkvist, A. & Usiello, A. Caffeine as a psychomotor stimulant: mechanism of action. Cell. Mol. Life Sci. 61, 857–872 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Honerjager, P. & Nawrath, H. Pharmacology of bipyridine phosphodiesterase III inhibitors. Eur. J. Anaesthesiol. Suppl. 5, 7–14 (1992).

    CAS  PubMed  Google Scholar 

  88. 88

    Kaneda, T., Takeuchi, Y., Matsui, H., Shimizu, K., Urakawa, N. & Nakajyo, S. Inhibitory mechanism of papaverine on carbachol-induced contraction in bovine trachea. J. Pharmacol. Sci. 98, 275–282 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Corbin, J. D. & Francis, S. H. Molecular biology and pharmacology of PDE-5-inhibitor therapy for erectile dysfunction. J. Androl. 24 (Suppl 6), 38–41 (2003).

    Article  Google Scholar 

  90. 90

    Beutler, A. S., Li, S., Nicol, R. & Walsh, M. J. Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 76, 3107–3115 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Calfee, D. P. & Hayden, F. G. New approaches to influenza chemotherapy: neuraminidase inhibitors. Drugs 56, 537–553 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Krasikov, V. V., Karelov, D. V. & Firsov, L. M. alpha-Glucosidases. Biochemistry (Mosc). 66, 267–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Guerciolini, R. Mode of action of orlistat. Int. J. Obes. Relat. Metab. Disord. 21 (Suppl 3), 12–23 (1997).

    Google Scholar 

  94. 94

    Wynn, G. H., Zapor, M. J., Smith, B. H., Wortmann, G., Oesterheld, J. R., Armstrong, S. C. & Cozza, K. L. Antiretrovirals, part 1: overview, history, and focus on protease inhibitors. Psychosomatics 45, 262–270 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Wegner, J. Biochemistry of serine protease inhibitors and their mechanisms of action: a review. J. Extra. Corpor. Technol. 35, 326–338 (2003).

    PubMed  Google Scholar 

  96. 96

    Konaklieva, M. I. β-lactams as inhibitors of serine enzymes. Curr. Med. Chem. Anti-Infect. Agents 1, 215–238 (2002).

    Article  CAS  Google Scholar 

  97. 97

    Nicolau, K. C., Boddy, C. N. C., Brase, S. & Winssinger, N. Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew. Chem., Int. Ed. Engl. 38, 2096–2152 (1999).

    Article  Google Scholar 

  98. 98

    Matagne, A., Dubus, A., Galleni, M. & Frere, J. M. The β-lactamase cycle. Nat. Prod. Rep. 16, 1–19 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Hirsh, J., Raschke, R., Warkentin, T. E., Dalen, J. E., Deykin, D. & Poller, L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 108 (Suppl. 4), 258–275 (1995).

    Article  Google Scholar 

  100. 100

    Nader, H. B., Lopes, C. C., Rocha, H. A., Santos, E. A. & Dietrich, C. P. Heparins and heparinoids: occurrence, structure and mechanism of antithrombotic and hemorrhagic activities. Curr. Pharm. Des. 10, 951–966 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Wolvekamp, M. C. & de Bruin, R. W. Diamine oxidase: an overview of historical, biochemical and functional aspects. Dig. Dis. 12, 2–14 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Weitz, J. I., Stewart, R. J. & Fredenburgh, J. C. Mechanism of action of plasminogen activators. Thromb. Haemost. 82, 974–982 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Bajaj, A. P. & Castellino, F. J. Activation of human plasminogen by equimolar levels of streptokinase. J. Biol. Chem. 252, 492–498 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Spronk, H. M., Govers-Riemslag, J. W. & ten Cate, H. The blood coagulation system as a molecular machine. Bioessays 25, 1220–1228 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Bauer, K. A. Fondaparinux sodium: a selective inhibitor of factor Xa. Am. J. Health Syst. Pharm. 58 (Suppl 2), 14–17 (2001).

    Article  Google Scholar 

  106. 106

    Nemec, K. & Schubert-Zsilavecz, M. From teprotide to captopril. Rational design of ACE inhibitors. Pharm. Unserer Zeit 32, 11–16 (2003).

    Article  CAS  Google Scholar 

  107. 107

    Pastel, D. A. Imipenem-cilastatin sodium, a broad-spectrum carbapenem antibiotic combination. Clin. Pharm. 5, 719–736 (1986).

    CAS  PubMed  Google Scholar 

  108. 108

    Bondeson, J. The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines. Gen. Pharmacol. 29, 127–150 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Adnane, L., Trail, P. A., Taylor, I., Wilhelm, S. M. Sorafenib (BAY 43–9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 407, 597–612 (2005).

    Article  CAS  Google Scholar 

  110. 110

    De la Baume, S., Brion, F., Dam- Trung-Tuong, M. & Schwartz, J. C. Evaluation of enkephalinase inhibition in the living mouse, using [3H]acetorphan as a probe. J. Pharmacol. Exp. Ther. 247, 653–660 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Reynolds, N. J. & Al-Daraji, W. I. Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin. Exp. Dermatol. 27, 555–561 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Patel, S., Martinez-Ripoll, M., Blundell, T. L. & Albert, A. Structural enzymology of Li+-sensitive/Mg2+-dependent phosphatases. J. Mol. Biol. 320, 1087–1094 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Spiegelberg, B. D, Dela Cruz, J., Law, T. H & York, J. D. Alteration of lithium pharmacology through manipulation of phosphoadenosine phosphate metabolism. J. Biol. Chem. 280, 5400–5405 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Tiede, I. et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J. Clin. Invest. 111, 1133–1145 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    El Ghachi, M., Bouhss, A., Blanot, D. & Mengin-Lecreulx, D. The bacA gene of Escherichia coli encodes an undecaprenyl pyrophosphate phosphatase activity. J. Biol. Chem. 279, 30106–30113 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Bartholini, G. & Pletscher, A. Decarboxylase inhibitors. Pharmacol. Ther. [B]. 1, 407–421 (1975).

    CAS  Google Scholar 

  117. 117

    Supuran, C. T., Scozzafava, A. & Casini, A. Carbonic anhydrase inhibitors. Med. Res. Rev. 23, 146–189 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Sonneville, A. Hypostamine (tritoqualine), a synthetic reference antihistaminic. Allerg. Immunol. (Paris) 20, 365–368 (1988).

    CAS  Google Scholar 

  119. 119

    Huang, Y., Pledgie, A., Casero, R. A. Jr. & Davidson, NE. Molecular mechanisms of polyamine analogs in cancer cells. Anticancer Drugs 16, 229–241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Chen, Z. et al. An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc. Natl Acad. Sci. USA 102, 12159–12164 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Thatcher, G. R., Nicolescu, A. C., Bennett, B. M. & Toader, V. Nitrates and NO release: contemporary aspects in biological and medicinal chemistry. Free Rad. Biol. Medic. 37, 1122–1143 (2004).

    Article  CAS  Google Scholar 

  122. 122

    Ignarro, L. J. After 130 years, the molecular mechanism of action of nitroglycerin is revealed. Proc. Natl Acad. Sci. USA 99, 7816–7817 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Kukovetz, W. R. & Holzmann, S. Cyclic GMP as the mediator of molsidomine-induced vasodilatation. Eur. J. Pharmacol. 122, 103–109 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Fenn, T. D., Stamper, G. F., Morollo, A. A. & Ringe, D. A side reaction of alanine racemase: transamination of cycloserine. Biochemistry 42, 5775–5783 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Drlica, K. & Malik, M. Fluoroquinolones: action and resistance. Curr. Top. Med. Chem. 3, 249–282 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Pizzolato, J. F. & Saltz, L. B. The camptothecins. Lancet 361, 2235–2242 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Meresse, P., Dechaux, E., Monneret, C. & Bertounesque, E. Etoposide: discovery and medicinal chemistry. Curr. Med. Chem. 11, 2443–2466 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Polak-Wyss, A., Lengsfeld, H., Oesterhelt, G. Effect of oxiconazole and Ro 14–4767/002 on sterol pattern in Candida albicans. Sabouraudia 23, 433–441 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Achari, A. et al. Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nature Struct. Biol. 4, 490–497 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev. Cancer 3, 330–338 (2003).

    Article  CAS  Google Scholar 

  131. 131

    Gilli, R., Lopez, C., Sari, J. C. & Briand, C. Thermodynamic study of the interaction of methotrexate, its metabolites, and new antifolates with thymidylate synthase: influence of FdUMP. Biochem. Pharmacol. 40, 2241–2246 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Su, J. G., Mansour, J. M. & Mansour, T. E. Purification, kinetics and inhibition by antimonials of recombinant phosphofructokinase from Schistosoma mansoni. Mol. Biochem. Parasitol. 81, 171–178 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Sehgal, S. N. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant. Proc. 35 (Suppl 3), 7–14 (2003).

    Article  CAS  Google Scholar 

  134. 134

    Foley, M. & Tilley, L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol. Ther. 79, 55–87 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Denning, D. W. Echinocandin antifungal drugs. Lancet 362, 1142–1151 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    McCormack, P. L. & Goa, K. L. Miglustat. Drugs 63, 2427–2434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Graham, M. L. Pegaspargase: a review of clinical studies. Adv. Drug Deliv. Rev. 55, 1293–1302 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Pea, F. Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and interactions. Contrib. Nephrol. 147, 35–46 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Dressler, D. & Adib Saberi, F. Botulinum toxin: mechanisms of action. Eur. Neurol. 53, 3–9 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Czapinski, P., Blaszczyk, B. & Czuczwar, S. J. Mechanisms of action of antiepileptic drugs. Curr. Top. Med. Chem. 5, 3–14 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Wafford, K. A. GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr. Opin. Pharmacol. 5, 47–52 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Hoffman, E. J. & Warren, E. W. Flumazenil: a benzodiazepine antagonist. Clin. Pharm. 12, 641–656 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Martin, R. J., Robertson, A. P. & Bjorn, H. Target sites of anthelmintics. Parasitology 114 (Suppl), 111–124 (1997).

    Google Scholar 

  144. 144

    Martin, R. J. Modes of action of anthelmintic drugs. Vet. J. 154, 11–34 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    McManus, M. C. Neuromuscular blockers in surgery and intensive care, Part 1. Am. J. Health Syst. Pharm. 58, 2287–2299 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Bowman, W. C. Neuromuscular block. Br. J. Pharmacol. 147 S1, 277–286 (2006).

    Article  CAS  Google Scholar 

  147. 147

    Samochocki, M. et al. Galantamine is an allosterically potentiating ligand of the human α4/β2 nAChR. Acta Neurol. Scand. Suppl. 176, 68–73 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Rogawski, M. A. & Wenk, G. L. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. C. N. S. Drug Rev. (Fall) 9, 275–308 (2003).

    Article  CAS  Google Scholar 

  149. 149

    Dahchour, A. & De Witte, P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog. Neurobiol. 60, 343–362 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Kress, H. G. Mechanisms of action of ketamine. Anaesthesist 46 (Suppl. 1), 8–19 (1997).

    Article  Google Scholar 

  151. 151

    Gautam, D. et al. Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice. Mol. Pharmacol. 66, 260–267 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Eglen, R. M., Choppin, A. & Watson, N. Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol. Sci. 22, 409–414 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Pitschner, H. F. et al. Selective antagonists reveal different functions of M cholinoceptor subtypes in humans. Trends Pharmacol. Sci. Suppl. 92–96 (1989).

  154. 154

    Hegde, S. S. et al. Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br. J. Pharmacol. 120, 1409–1418. (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Fredholm, B. B., Chen, J. F., Masino, S. A. & Vaugeois, J. M. Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu. Rev. Pharmacol. Toxicol. 45, 385–412 (2005).

    Article  CAS  Google Scholar 

  156. 156

    Schumacher, B., Scholle, S., Holzl, J., Khudeir, N., Hess, S. & Muller, C. E. Lignans isolated from valerian: identification and characterization of a new olivil derivative with partial agonistic activity at A1 adenosine receptors. J. Nat. Prod. 65, 1479–1485 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Fisone, G., Borgkvist, A. & Usiello, A. Caffeine as a psychomotor stimulant: mechanism of action. Cell. Mol. Life Sci. 61, 857–872 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Ruffolo, R. R., Bondinell, W. Jr. & Hieble, J. P. α- and β-adrenoceptors: from the gene to the clinic. 2. Structure–activity relationships and therapeutic applications. J. Med. Chem. 38, 3681–3716 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Hieble, J. P., Bondinell, W. & Ruffolo, R. R. From the gene to the clinic. 1. Molecular biology and adrenoceptor classification. J. Med. Chem. 38, 3415–3444 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Silberstein, S. D. The pharmacology of ergotamine and dihydroergotamine. Headache 37 (Suppl. 1), 15–25 (1997).

    PubMed  PubMed Central  Google Scholar 

  161. 161

    Burnier, M. Angiotensin II type 1 receptor blockers. Circulation 13, 904–12 (2001).

  162. 162

    Brown, E. M. Is the calcium receptor a molecular target for the actions of strontium on bone? Osteoporo. Int. 14 (Suppl 3), 25–34 (2003).

    Article  CAS  Google Scholar 

  163. 163

    Nemeth, E. F. et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J. Pharmacol. Exp. Ther. 308, 627–635 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Grotenhermen, F. Pharmacology of cannabinoids. Neuro. Endocrinol. Lett. 25, 14–23 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Nicosia, S. Pharmacodynamic properties of leukotriene receptor antagonists. Monaldi Arch. Chest Dis. 54, 242–246 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Vallone, D., Picetti, R. & Borrelli, E. Structure and function of dopamine receptors. Neurosci. Biobehav. Rev. 24, 125–132 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Clozel, M. et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 270, 228–235 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Hill, D. R. & Bowery, N. G. 3H-Baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature 290, 149–152 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Unson, C. G. Molecular determinants of glucagon receptor signaling. Biopolymers 66, 218–235 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Keating, G. M. Exenatide. Drugs 65, 1681–1692 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Simons, F. E. Advances in H1-antihistamines. N. Engl. J. Med. 351, 2203–2217 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Mills, J. G. & Wood, J. R. The pharmacology of histamine H2-receptor antagonists. Methods Find. Exp. Clin. Pharmacol. 11 (Suppl 1), 87–95 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Pasternak, G. W. Molecular biology of opioid analgesia. J. Pain Symptom. Manage. 29 (Suppl.) S2–S9 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Surratt, C. K. & Adams, W. R. G protein-coupled receptor structural motifs: relevance to the opioid receptors. Curr. Top. Med. Chem. 5, 315–324 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Diemunsch, P. & Grelot, L. Potential of substance P antagonists as antiemetics. Drugs 60, 533–546 (2000).

    Article  CAS  Google Scholar 

  176. 176

    Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid receptors: structures, properties, and functions. Physiol. Rev. 79, 1193–1226 (1999).

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Krauss, A. H. & Woodward, D. F. Update on the mechanism of action of bimatoprost: a review and discussion of new evidence. Surv. Ophthalmol. 49 (Suppl. 1), 5–11 (2004).

    Article  Google Scholar 

  178. 178

    Herbert, J. M. & Savi, P. P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin. Vasc. Med. 3, 113–122 (2003).

    Article  PubMed  Google Scholar 

  179. 179

    Tunnicliff, G. Molecular basis of buspirone's anxiolytic action. Pharmacol. Toxicol. 69, 149–156 (1991).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Ahn, A. H. & Basbaum, A. I. Where do triptans act in the treatment of migraine? Pain 115, 1–4 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Meltzer, H. Y., LI, Z., Kaneda, Y. & Ichikawa, J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 1159–1172 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. 182

    Blower, P. R. Granisetron: relating pharmacology to clinical efficacy. Support Care Cancer 11, 93–100 (2003).

    PubMed  Google Scholar 

  183. 183

    Galligan, J. J. & Vanner, S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol. Motil. 17, 643–653 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. 184

    Chini, B. & Fanelli, F. Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family. Exp. Physiol. 85 Spec. No 59S–66S (2000).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Kam, P. C., Williams, S. & Yoong, F. F. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia 59, 993–1001 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. 186

    Kopchick, J. J. Discovery and mechanism of action of pegvisomant. Eur. J. Endocrinol. 148 (Suppl. 2), 21–25 (2003).

    Article  Google Scholar 

  187. 187

    Zhu, Y. & D'Andrea, A. D. The molecular physiology of erythropoietin and the erythropoietin receptor. Curr. Opin. Hematol. 1, 113–118 (1994).

    CAS  PubMed  Google Scholar 

  188. 188

    Crawford, J. Neutrophil growth factors. Curr. Hematol. Rep. 1, 95–102 (2002).

    PubMed  Google Scholar 

  189. 189

    Sylvester, R. K. Clinical applications of colony-stimulating factors: a historical perspective. Am. J. Health Syst. Pharm. 59, Suppl 2, S6–12 (2002)

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Fleischmann, R., Stern, R. & Iqbal, I. Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. Expert. Opin. Biol. Ther. 4, 1333–1344 (2004).

    Article  CAS  PubMed  Google Scholar 

  191. 191

    Schmidinger, M., Hejna, M. & Zielinski, C. C. Aldesleukin in advanced renal cell carcinoma. Expert. Rev. Anticancer Ther. 4, 957–80 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. 192

    Cole, P. & Rabasseda, X. The soluble tumor necrosis factor receptor etanercept: a new strategy for the treatment of autoimmune rheumatic disease. Drugs Today (Barc.) 40, 281–324 (2004).

    Article  CAS  Google Scholar 

  193. 193

    Topol, E. J., Byzova, T. V. & Plow, E. F. Platelet GPIIb-IIIa blockers. Lancet 353, 227–231 (1999).

    Article  CAS  PubMed  Google Scholar 

  194. 194

    Accili, D., Nakae, J. & Flier, J. S. in Diabetes Mellitus — A Fundamental and Clinical Text 3rd edn (eds LeRoith, D., Taylor, S. I. & Olefsky, J. M.) (Lippincott Williams & Wilkins, Philadelphia, 2003).

    Google Scholar 

  195. 195

    Jiang, G. & Zhang, B. B. Modulation of insulin signalling by insulin sensitizers. Biochem. Soc. Trans. 33, 358–361 (2005)

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Rogerson, F. M, Brennan, F. E. & Fuller, P. J. Mineralocorticoid receptor binding, structure and function. Mol. Cell. Endocrinol. 217, 203–212 (2004).

    Article  CAS  PubMed  Google Scholar 

  197. 197

    Necela, B. M. & Cidlowski, J. A. Crystallization of the human glucocorticoid receptor ligand binding domain: a step towards selective glucocorticoids. Trends Pharmacol. Sci. 24, 58–61 (2003).

    Article  CAS  PubMed  Google Scholar 

  198. 198

    Li, X. & O'Malley, B. W. Unfolding the action of progesterone receptors. J. Biol. Chem. 278, 39261–39264 (2003).

    Article  CAS  PubMed  Google Scholar 

  199. 199

    Katzenellenbogen, B. S. et al. Molecular mechanisms of estrogen action: selective ligands and receptor pharmacology. J. Steroid Biochem. Mol. Biol. 74, 279–285 (2000).

    Article  CAS  PubMed  Google Scholar 

  200. 200

    Levenson, A. S. & Jordan, V. C. Selective oestrogen receptor modulation: molecular pharmacology for the millennium. Eur. J. Cancer 35, 1628–1639 (1999).

    Article  CAS  Google Scholar 

  201. 201

    Gobinet, J., Poujol, N. & Sultan, Ch. Molecular action of androgens. Mol. Cell. Endocrinol. 198, 15–24 (2002).

    Article  CAS  Google Scholar 

  202. 202

    Roy, A. K. et al. Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Ann. N. Y. Acad. Sci. 949, 44–57 (2001).

    Article  CAS  Google Scholar 

  203. 203

    Gao, W., Bohl, C. E. & Dalton, J. T. Chemistry and structural biology of androgen receptor. Chem. Rev. 105(9), 3352–3370 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Neumann, F. The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research. Exp. Clin. Endocrinol. 102, 1–32 (1994).

    Article  CAS  Google Scholar 

  205. 205

    Carlberg, C. Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res. 164, 29–42 (2003)

    Article  CAS  Google Scholar 

  206. 206

    Pinette, K. V., Yee, Y. K., Amegadzie, B. Y. & Nagpal, S. Vitamin D receptor as a drug discovery target. Mini Rev. Med. Chem. 3, 193–204 (2003).

    Article  CAS  Google Scholar 

  207. 207

    Minucci, S. & Ozato, K. Retinoid receptors in transcriptional regulation. Curr. Opin. Genet. Dev. 6, 567–574 (1996).

    Article  CAS  Google Scholar 

  208. 208

    Zwermann, O., Schulte, D. M., Reincke, M. & Beuschlein, F. ACTH 1–24 inhibits proliferation of adrenocortical tumors in vivo. Eur. J. Endocrinol. 153, 435–444 (2005).

    Article  CAS  Google Scholar 

  209. 209

    The Retinoids. Biology, Chemistry and Medicine (eds Mangelsdorf, D. J. et al.) 319–349 (Raven Press, New York, 1994).

  210. 210

    Czernielewski, J., Michel, S., Bouclier, M., Baker, M. & Hensby, J. C. Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne. J. Eur. Acad. Dermatol. Venereol. 15 (Suppl 3), 5–12 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  211. 211

    Duriez, P. Mechanism of actions of statins and fibrates. Therapie 58, 5–14 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Staels, B. et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98, 2088–2093 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Willson, T. M. et al. The structure–activity relationship between peroxisome proliferator-activated receptor agonism and the antihyperglycemic activity of thiazolidinediones. J. Med. Chem. 39, 665–668 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Brent, G. A. The molecular basis of thyroid hormone action. N. Engl. J. Med. 331, 847–853 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

    Saier Lab Bioinformatics Group. Transport Classification Database, [online] (2006).

  216. 216

    Schmidt, D. & Elger, C. E. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav. 5, 627–635 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  217. 217

    Greenberg, R. M. Are Ca2+ channels targets of praziquantel action? Int. J. Parasitol. 35, 1–9 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Moosmang, S., Lenhardt, P., Haider, N., Hofmann, F. & Wegener, J. W. Mouse models to study L-type calcium channel function. Pharmacol. Ther. 106, 347–355 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

    Triggle, D. J. 1, 4-Dihydropyridines as calcium channel ligands and privileged structures. Cell. Mol. Neurobiol. 23, 293–303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. 220

    Striessnig, J., Grabner, M., Mitterdorfer, J., Hering, S., Sinnegger, M. J. & Glossmann, H. Structural basis of drug binding to L-Ca2+ channels. Trends Pharmacol. Sci. 19, 108–115 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Meredith, P. A. Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity. Expert Opin. Investig. Drugs 8, 1043–1062 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. 222

    Dworkin, R. H. & Kirkpatrick, P. Pregabalin. Nature Rev. Drug Discov. 4, 455–456 (2005).

    Article  CAS  Google Scholar 

  223. 223

    Ninomiya, T., Takano, M., Haruna, T., Kono, Y. & Horie, M. Verapamil, a Ca2+ entry blocker, targets the pore-forming subunit of cardiac type KATP channel (Kir6. 2). J. Cardiovasc. Pharmacol. 42, 161–168 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. 224

    Gomora, J. C., Daud, A. N., Weiergraber, M. & Perez-Reyes, E. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol. Pharmacol. 60, 1121–1132 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. 225

    Tamargo, J., Caballero, R., Gomez, R., Valenzuela, C. & Delpon, E. Pharmacology of cardiac potassium channels. Cardiovasc. Res. 62, 9–33 (2004).

    Article  CAS  Google Scholar 

  226. 226

    Ashcroft, F. M. & Gribble, F. M. New windows on the mechanism of action of K(ATP) channel openers. Trends Pharmacol. Sci. 21, 439–445 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. 227

    Davies, M. P., McCurrie, J. R. & Wood, D. Comparative effects of K+ channel modulating agents on contractions of rat intestinal smooth muscle. Eur. J. Pharmacol. 297, 249–256 (1996).

    Article  CAS  Google Scholar 

  228. 228

    Hu, S., Boettcher, B. R. & Dunning, B. E. The mechanisms underlying the unique pharmacodynamics of nateglinide. Diabetologia 46 (Suppl. 1), M37–43 (2003).

    Article  CAS  Google Scholar 

  229. 229

    Bryan, J., Crane, A., Vila-Carriles, W. H., Babenko, A. P. & Aguilar-Bryan, L. Insulin secretagogues, sulfonylurea receptors and K(ATP) channels. Curr. Pharm. Des. 11, 2699–2716 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    Kodama, I., Kamiya, K. & Toyama, J. Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am. J. Cardiol. 84, 20R–28R (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Roden, D. M. Antiarrhythmic drugs: past, present, and future. J. Cardiovasc. Electrophysiol. 14, 1389–1396 (2003).

    Article  Google Scholar 

  232. 232

    Ambrosio, A. F., Soares-Da-Silva, P., Carvalho, C. M. & Carvalho, A. P. Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2–093, and BIA 2–024. Neurochem. Res. 27, 121–130 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Falk, R. H. & Fogel, R. I. Flecainide. J. Cardiovasc. Electrophysiol. 5, 964–981 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Coulter, D. A. Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? J. Child Neurol. 12 (Suppl. 1), S2–S9 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  235. 235

    Southam, E. et al. Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo. Eur. J. Pharmacol. 519, 237–245 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Lou, B. S., Lin, T. H. & Lo, C. Z. The interactions of phenytoin and its binding site in DI-S6 segment of Na+ channel voltage-gated peptide by NMR spectroscopy and molecular modeling study. J. Pept. Res. 66, 27–38 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

    Faber, T. S. & Camm, A. J. The differentiation of propafenone from other class Ic agents, focusing on the effect on ventricular response rate attributable to its beta-blocking action. Eur. J. Clin. Pharmacol. 51, 199–208 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    White, H. S. Molecular pharmacology of topiramate: managing seizures and preventing migraine. Headache 45 (Suppl. 1), S48–S56 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  239. 239

    Gurvich, N. & Klein, P. S. Lithium and valproic acid: parallels and contrasts in diverse signaling contexts. Pharmacol. Ther. 96, 45–66 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. 240

    Kang, M., Lisk, G., Hollingworth, S., Baylor, S. M. & Desai, S. A. Malaria parasites are rapidly killed by dantrolene derivatives specific for the plasmodial surface anion channel. Mol. Pharmacol. 68, 34–40 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Parness, J. & Palnitkar, S. S. Identification of dantrolene binding sites in porcine skeletal muscle sarcoplasmatic reticulum. J. Biol. Chem. 270, 18465–18472 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. 242

    Zygmunt, P. M., Chuang, H., Movahed, P., Julius, D. & Hogestatt, E. D. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur. J. Pharmacol. 396, 39–42 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. 243

    Dutzler, R. The structural basis of ClC chloride channel function. Trends Neurosci. 27, 315–320 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. 244

    Reinsprecht, M., Pecht, I., Schindler, H. & Romanin, C. Potent block of Cl− channels by antiallergic drugs. Biochem. Biophys. Res. Commun. 188, 957–963 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. 245

    Cheeseman, C. L., Delany, N. S., Woods, D. J. & Wolstenholme, A. J. High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel. Mol. Biochem. Parasitol. 114, 161–168 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Saier Lab Bioinformatics Group, Transport Classicication Database, http://www.tcdb.org

  247. 247

    Gamba, G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol. Rev. 85, 423–493 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. 248

    Ellison, D. H. The thiazide-sensitive Na-Cl cotransporter and human disease: reemergence of an old player. J. Am. Soc. Nephrol. 14, 538–540 (2003).

    PubMed  PubMed Central  Google Scholar 

  249. 249

    Plata, C., Meade, P., Hall, A., Welch, R. C., Vazquez, N., Hebert, S. C., Gamba, G. Alternatively spliced isoform of apical Na+-K+-Cl− cotransporter gene encodes a furosemide-sensitive Na+-Cl−cotransporter. Am. J. Physiol. Renal. Physiol. 280, F574–582 (2001).

    Article  Google Scholar 

  250. 250

    Kleyman, T. R., Sheng, S., Kosari, F. & Kieber-Emmons, T. Mechanism of action of amiloride: a molecular prospective. Semin. Nephrol. 19, 524–532 (1999).

    CAS  Google Scholar 

  251. 251

    Ismailov, I. I. et al. Identification of an amiloride binding domain within the alpha-subunit of the epithelial Na+ channel. J. Biol. Chem. 272, 21075–21083 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. 252

    Priewer, H. & Ullrich, F. Potassium and magnesium retaining triamterene derivatives. Pharmazie 52, 179–181 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253

    Eckstein-Ludwig, U. et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424, 957–961 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. 254

    Olbe, L., Carlsson, E. & Lindberg, P. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nature Rev. Drug Discov. 2, 132–139 (2003).

    Article  CAS  Google Scholar 

  255. 255

    Paula, S., Tabet, M. R. & Ball, W. J. Jr. Interactions between cardiac glycosides and sodium/potassium-ATPase: three-dimensional structure-activity relationship models for ligand binding to the E2-Pi form of the enzyme versus activity inhibition. Biochemistry 44, 498–510 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. 256

    Garcia-Calvo, M. et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc. Natl Acad. Sci. USA 102, 8132–8137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. 257

    Goldberg, N. R., Beuming, T., Soyer, O. S., Goldstein, R. A., Weinstein, H. & Javitch, J. A. Probing conformational changes in neurotransmitter transporters: a structural context. Eur. J. Pharmacol. 479, 3–12 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. 258

    Saier, Jr., M. H. A functional-phylogenetic system for the classification of transport proteins. J. Cell Biochem. Suppl. 32–33, 84–94 (1999).

    Article  Google Scholar 

  259. 259

    Owens, M. J., Morgan, W. N., Plott, S. J. & Nemeroff, C. B. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J. Pharmacol. Exp. Ther. 283, 1305–1322 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. 260

    Blakely, R. D., De Felice, L. J. & Hartzell, H. C. Molecular physiology of norepinephrine and serotonin transporters. J. Exp. Biol. 196, 263–281 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

    Bondarev, M. L., Bondareva, T. S., Young, R. & Glennon, R. A. Behavioral and biochemical investigations of bupropion metabolites. Eur. J. Pharmacol. 474, 85–93 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    Beique, J. C., Lavoie, N., de Montigny, C. & Debonnel, G. Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur. J. Pharmacol. 349, 129–132 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    Henry, J. P. et al. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules. J. Exp. Biol. 196, 251–262 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Deupree, J. D. & Weaver, J. A. Identification and characterization of the catecholamine ransporter in bovine chromaffin granules using [3H]reserpine. J. Biol. Chem. 259, 10907–10912 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265

    Dervan, P. B. Molecular recognition of DNA by small molecules. Bioorg. Med. Chem. 9, 2215–2235 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. 266

    Mattes, W. B., Hartley, J. A. & Kohn, K. W. DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Res. 14, 2971–2987 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. 267

    Maccubbin, A. E., Caballes, L., Scappaticci, F., Struck, R. F. & Gurtoo, H. L. 32P-postlabeling analysis of binding of the cyclophosphamide metabolite, acrolein, to DNA. Cancer Commun. 2, 207–211 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. 268

    Sanada, M., Takagi, Y., Ito, R. & Sekiguchi, M. Killing and mutagenic actions of dacarbazine, a chemotherapeutic alkylating agent, on human and mouse cells: effects of Mgmt and Mlh1 mutations. DNA Repair (Amst.) 3, 413–420 (2004).

    Article  CAS  Google Scholar 

  269. 269

    Delalande, O., Malina, J., Brabec, V. & Kozelka, J. Chiral differentiation of DNA adducts formed by enantiomeric analogues of antitumor cisplatin is sequence-dependent. Biophys. J. 88, 4159–4169 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. 270

    Siddik, Z. H. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265–7279 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. 271

    Temperini, C. et al. The crystal structure of the complex between a disaccharide anthracycline and the DNA hexamer d(CGATCG) reveals two different binding sites involving two DNA duplexes. Nucleic Acids Res. 31, 1464–1469 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. 272

    Hecht, S. M. Bleomycin: new perspectives on the mechanism of action. J. Nat. Prod. 63, 158–168 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. 273

    Lamp, K. C., Freeman, C. D., Klutman, N. E. & Lacy, M. K. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin. Pharmacokinet. 36, 353–373 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. 274

    Carter, A. P. et al. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407, 340–348 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. 275

    Schlunzen, F. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413, 814–821 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

    Colca, J. R. et al. Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics. J. Biol. Chem. 278, 21972–21979 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. 277

    Duflos, A., Kruczynski, A., Barret, J. M. Novel aspects of natural and modified vinca alkaloids. Curr. Med. Chem. Anti-Canc. Agents 2, 55–70 (2002).

    Article  CAS  Google Scholar 

  278. 278

    Lipp, H. P. & Bokemeyer, C. The action and toxicity of taxanes. Pharm. Unserer Zeit 34, 128–137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. 279

    Molad, Y. Update on colchicine and its mechanism of action. Curr. Rheumatol. Rep. 4, 252–256 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  280. 280

    Hermann, T. Drugs targeting the ribosome. Curr. Opin. Struct. Biol. 15, 355–366 (2005).

    Article  CAS  Google Scholar 

  281. 281

    Anokhina, M. M., Barta, A., Nierhaus, K. H., Spiridonova, V. A. & Kopylov, A. M. Mapping of the second tetracycline binding site on the ribosomal small subunit of E. coli. Nucleic Acids Res. 32, 2594–2597 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. 282

    Spizek, J., Novotna, J. & Rezanka, T. Lincosamides: chemical structure, biosynthesis, mechanism of action, resistance, and applications. Adv. Appl. Microbiol. 56, 121–154 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. 283

    Harms, J. M., Schlunzen, F., Fucini, P., Bartels, H. & Yonath, A. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol. 2, 4 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  284. 284

    Nygren, P., Sorbye, H., Osterlund, P. & Pfeiffer, P. targeted drugs in metastatic colorectal cancer with special emphasis on guidelines for the use of bevacizu-mab and cetuximab. Acta Oncol. 44, 203–217 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. 285

    Muhsin, M., Graham, J. & Kirkpatrick, P. Bevacizumab. Nature Rev. Drug Discov. 3, 995–996 (2004).

    Article  CAS  Google Scholar 

  286. 286

    Marecki, S. & Kirkpatrick, P. Efalizumab. Nature Rev. Drug Discov. 3, 473–474 (2004).

    Article  CAS  Google Scholar 

  287. 287

    Goldberg, R. M. Cetuximab. Nature Rev. Drug Discov. 4, S10–S11 (2005).

    Article  Google Scholar 

  288. 288

    Albanell, J., Codony, J., Rovira, A., Mellado, B. & Gascon, P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv. Exp. Med. Biol. 532, 253–268 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. 289

    Davis, L. A. Omalizumab: a novel therapy for allergic asthma. Ann. Pharmacother. 38, 1236–1242 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. 290

    Hooks, M. A., Wade, C. S. & Millikan, W. J., Jr. Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation. Pharmacotherapy 11, 26–37 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291

    Witzig, T. E. Yttrium-90-ibritumomab tiuxetan radioimmunotherapy: a new treatment approach for B-cell non-Hodgkin's lymphoma. Drugs Today (Barc.) 40, 111–119 (2004).

    Article  CAS  Google Scholar 

  292. 292

    Multani, P. & White, C. A. Rituximab. Cancer Chemother. Biol. Response Modif. 21, 235–258 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. 293

    Linenberger, M. L. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 19, 176–182 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. 294

    Frampton, J. E. & Wagstaff, A. J. Alemtuzumab. Drugs 63, 1229–1243 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. 295

    Scott, L. J. & Lamb, H. M. Palivizumab. Drugs 58, 305–313 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. 296

    Kapic, E., Becic, F. & Kusturica, J. Basiliximab, mechanism of action and pharmacological properties. Med. Arh. 58, 373–376 (2004).

    PubMed  Google Scholar 

  297. 297

    Carswell, C. I., Plosker, G. L. & Wagstaff, A. J. Daclizumab: a review of its use in the management of organ transplantation. BioDrugs 15, 745–773 (2001).

    Article  CAS  PubMed  Google Scholar 

  298. 298

    Bain, B. & Brazil, M. Adalimumab. Nature Rev. Drug Discov. 2, 693–694 (2003).

    Article  CAS  Google Scholar 

  299. 299

    Winterfield, L. S. & Menter, A. Infliximab. Dermatol. Ther. 17, 409–426 (2004).

    Article  PubMed  Google Scholar 

  300. 300

    Faulds, D. & Sorkin, E. M. Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease. Drugs 48, 583–598 (1994).

    Article  CAS  PubMed  Google Scholar 

  301. 301

    Noseworthy, J. H. & Kirkpatrick, P. Natalizumab. Nature Rev. Drug Discov. 4, 101–102 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the following colleagues for help with compiling the first draft: T. Buβ, L. Ann Bailey, H. Morck, M. Ramadan and T. Rogosch (Fachbereich Pharmazie, Universität Marburg, Germany), and C. Oehler and R. Schneider (Institut für Pharmazie, Universität Halle, Germany).

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  1. Institut für Pharmazie, Martin-Luther-Universität, Halle-Wittenberg, 06120, Halle, Germany

    Peter Imming, Christian Sinning & Achim Meyer

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Correspondence to Peter Imming.

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Imming, P., Sinning, C. & Meyer, A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 5, 821–834 (2006). https://doi.org/10.1038/nrd2132

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