Perspectives in Drug Discovery and Design

, Volume 9, Issue 0, pp 225–252

Similarity and Dissimilarity: A Medicinal Chemist's View

  • Hugo Kubinyi


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    BÖhm, H.-J., Klebe, G. and Kubinyi, H., Wirkstoffdesign. Der Weg zum Arzneimittel, Spektrum Akademischer Verlag, Heidelberg, 1996.Google Scholar
  2. 2.
    Wermuth, C.G. (Ed.), The Practice of Medicinal Chemistry, Academic Press, London, 1996.Google Scholar
  3. 3.
    Wolff, M.E. (Ed.), Burger's Medicinal Chemistry, 5th Ed., Vol. 1, John Wiley, New York, 1995.Google Scholar
  4. 4.
    Weber, L., Wallbaum, S., Broger, C. and Gubernator, K., Optimization of the biological activity of combinatorial compound libraries by a genetic algorithm, Angew. Chem., 107 (1995) 2452–2454; Angew. Chem. Intern. Ed., 34 (1995) 2280–2282.Google Scholar
  5. 5.
    Singh, J., Ator, M.A., Jaeger, E.P., Allen, M.P., Whipple, D.A., Soloweij, J.E., Chowdhary, S. and Treasurywala, A.M., Application of genetic algorithms to combinatorial synthesis: a computational approach to lead identification and lead optimization, J. Am. Chem. Soc., 118 (1996), 1669–1676.Google Scholar
  6. 6.
    Morgan, B.P., Holland, D.R., Matthews, B.W. and Barlett, P.A., Structure-based design of an inhibitor of the zinc peptidase thermolysin, J. Am. Chem. Soc., 116 (1994) 3251–3260.Google Scholar
  7. 7.
    Kaminski, J.J., Wallmark, B., Briving, C. and Anderson, B.-M., Antiulcer agents: 5. inhibition of gastric H+ /K+-ATPase by substituted Imidazo[1,2-a]pyridines and related analogs and its implications in modeling the high affinity potassium ion binding site of the gastric proton pump enzyme, J. Med. Chem., 34 (1991) 533–541.Google Scholar
  8. 8.
    Lauri, G. and Barlett, P.A., CAVEAT: A program to facilitate the design of organic molecules, J. Comput.-Aided Mol. Design, 8 (1994) 51–66.Google Scholar
  9. 9.
    Kaplan, A.P. and Barlett, P.A., Synthesis and evaluation of an inhibitor of carboxypeptidase A with a Ki value in the femtomolar range, Biochemistry, 30 (1991) 8165–8170.Google Scholar
  10. 10.
    Barlett, P.A. and Marlowe, C.K., Evaluation of intrinsic binding energy from a hydrogen bonding group in an enzyme inhibitor, Science, 235 (1987) 569–571.Google Scholar
  11. 11.
    Morgan, B.P., Scholtz, J.M., Ballinger, M.D., Zipkin, I.D. and Barlett, P.A., Differential binding energy: A detailed evaluation of the influence of hydrogen-bonding and hydrophobic groups on the inhibition of thermolysin by phosphorous-containing inhibitors, J. Am. Chem. Soc., 113 (1991) 297–307.Google Scholar
  12. 12.
    Merz, K.M. and Kollman, P.A., Free energy perturbation of the inhibition of thermolysin: Prediction of the free energy of binding of a new inhibitor, J. Am. Chem. Soc., 111 (1989) 5649–5658.Google Scholar
  13. 13.
    Shuman, R.T., Rothenberger, R.B., Campbell, C.S., Smith, G.F., Gifford-Moore, D.S. and Gesellchen, P.D., A series of highly selective thrombin inhibitors, In Smith, J.A. and Rivier, J.E. (Eds) Peptides - chemistry and biology, Proceedings of the 12th American Peptide Symposium, Cambridge, MA, U.S.A., 1991, ESCOM Science Publishers B.V., Leiden, 1992, pp. 801–802.Google Scholar
  14. 14.
    Stanton, J.L., Ksander, G.M., de Jesus, R. and Sperbeck, D.M., The effect of heteroatom substitution on a series of phosphonate inhibitors of neutral endopeptidase 24.11, Bioorg. Med. Chem. Lett., 4 (1994) 539–542.Google Scholar
  15. 15.
    Weber, A.E., Steiner, M.G., Krieter, P.A., Colletti, A.E., Tata, J.R., Halgren, T.A., Ball, R.G., Doyle, J.J., Schorn, T.W., Stearns, R.A., Miller, R.R., Siegl, P.K.S., Greenlee, W.J. and Patchett, A.A., Highly potent, orally active diester macrocyclic human renin inhibitors, J. Med. Chem. 35 (1992) 3755–3773.Google Scholar
  16. 16.
    Wolfenden, R. and Kati, W.M., Testing the limits of protein-ligand binding discrimination with transition-state analogue inhibitors, Acc. Chem. Res., 24 (1991) 209–215.Google Scholar
  17. 17.
    Xiang, S., Short, S.A., Wolfenden, R. and Carter, C.W., Transition-state selectivity for a single hydroxyl group during catalysis by cytidine deaminase, Biochemistry, 34 (1995) 4516–4523.Google Scholar
  18. 18.
    Parker, E.M., Grisel, D.A., Iben, L.G. and Shapiro, R.S., A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-Hydroxytryptamine 1B receptors, J. Neurochem., 60 (1993) 380–383.Google Scholar
  19. 19.
    Clozel, J.-P. and Fischli, W., Discovery of remikiren as the first orally active renin inhibitor, Arzneim.-Forsch. (Drug Research), 43 (1993) 260–262.Google Scholar
  20. 20.
    Li, R.-L., Hansch, C., Matthews, D., Blaney, J.M., Langridge, R., Delcamp, T.J., Susten, S.S. and Freisheim, J.H., A comparison by QSAR, crystallography, and computer graphics of the inhibition of various dihydrofolate reductases by 5-(X-Benzyl)-2,4-diaminopyrimidines, Quant. Struct.-Act. Relat., 1 (1982) 1–7.Google Scholar
  21. 21.
    Li, Z., Nguyen, D.T., Kitson, D.H., Bajorath, J., Kraut, J. and Hagler, A.T., Origin of trimethoprim's pharmacologic activity and differential binding to E. coli and chicken liver dihydrofolate reductases: Long-range electrostatic non-’lock and key’ specificity, Abstract of Presentations, Scientific Seminar Tour 1993, BIOSYM, San Diego, CA, U.S.A., 1993, pp. 14–19.Google Scholar
  22. 22.
    Roques, B.P., Nobel, F., Daugé, V., Fournié-Zaluski, M. and Beaumont, A., Neutral endopeptidase 24.11: Structure, inhibition and experimental and clinical pharmacology, Pharmacol. Rev., 45 (1993) 87–146.Google Scholar
  23. 23.
    Roderick, S.L., Fournié-Zaluski, M.C., Roques, B.P. and Matthews, B.W., Thiorphan and retro-thiorphan display equivalent interactions when bound to crystalline thermolysin, Biochemistry, 28 (1989) 1493–1497.Google Scholar
  24. 24.
    Slusarchyk, W.A., Robl, J.A., Taunk, P.C., Asaad, M.M., Bird, J.E., DiMarco, J. and Pan, Y., Dual met-alloprotease inhibitors: V. Utilization of bicyclic azepinothiazolidines and azepinonetetrahydrothiazenes in constrained peptidomimetics of mercaptoacyl dipeptides, Bioorg. Med. Chem. Lett., 7 (1995) 753–758.Google Scholar
  25. 25.
    Hofmann, A., LSD - mein Sorgenkind, dtv/Klett-Cotta, Munich, 1993.Google Scholar
  26. 26.
    Hanson, D.J., Dioxin toxicity: New studies prompt debate, regulatory action, Chem. Eng. News, 12 August 1991, 7–14.Google Scholar
  27. 27.
    Mattos, C. and Ringe, D., Multiple binding modes, In Kubinyi, H. (Ed.) 3D QSAR in drug design: Theory methods and applications, ESCOM Science Publishers B.V., Leiden, 1993 pp. 226–254.Google Scholar
  28. 28.
    Meyer, E.F., Botos, I., Scapozza, L. and Zhang, D., Backward binding and other structural surprises, Persp. Drug Discov. Design, 3 (1993) 168–195.Google Scholar
  29. 29.
    BÖhm, H.-J. and Klebe, G., What can we learn from molecular recognition in protein-ligand complexes for the design of new drugs?, Angew. Chem., 108 (1996) 2750–2778; Angew. Chem. Intern. Edit., 35 (1996), 2588–2614.Google Scholar
  30. 30.
    Montgomery, J.A. and Niwas, S., Structure-based drug design, Chemtech, 23 (1993) 30–37.Google Scholar
  31. 31.
    Montgomery, J.A., and Secrist III, J.A., PNP Inhibitors, Persp. Drug Discov. Design, 2 (1994) 205–220.Google Scholar
  32. 32.
    Kester, W.R., and Matthews, B.W., Crystallographic study of the binding of dipeptide inhibitors to thermolysin: Implications for the mechanism of catalysis, Biochemistry, 16 (1977) 2506–2516.Google Scholar
  33. 33.
    Badger, J., Minor, I., Kremer, M.J., Oliveira, M.A., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishnaswamy, S., Luo, M., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Dutko, F.J., Fancher, M., Rueckert, R.R. and Heinz, B.A., Structural analysis of a series of antiviral agents complexed with human rhinovirus 14, Proc. Natl. Acad. Sci. USA, 85 (1988) 3304–3308.Google Scholar
  34. 34.
    Diana, G.D., Treasurywala, A.M., Bailey, T.R., Oglesby, R.C., Pevear, D.C. and Dutko, F.J., A model for compounds active against human rhinovirus-14 based on X-ray crystallography data, J. Med. Chem., 33 (1990) 1306–1311.Google Scholar
  35. 35.
    Bystroff, C., Oatley, S.J. and Kraut, J., Crystal structures of Eschericha coli dihydrofolate reductase: The NADP + holoenzyme and the folate NADP + ternary complex: Substrate binding and a model for the transition state, Biochemistry, 29 (1990) 3263–3277.Google Scholar
  36. 36.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin R.C. and Kraut, J., Crystal structure of Eschericha coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 Å resolution, J. Biol. Chem., 257 (1982) 13650–13662.Google Scholar
  37. 37.
    Poulos, T.L. and Howard, A.J., Crystal structures of metyrapone-and phenylimidazole-inhibited complexes of cytochrome P-450 cam, Biochemistry, 26 (1987) 8165–8174.Google Scholar
  38. 38.
    Mattos, C., Rasmussen, B., Ding, X., Petsko, G.A. and Ringe, D., Analogous inhibitors of elastase do not always bind analogously, Nature, Struct. Biol., 1 (1994) 55–58.Google Scholar
  39. 39.
    Massumoto, O., Taga, T., Matsushima, M., Higashi, T. and Machida, K., Multiple binding of inhibitors in the complex formed by bovine trypsin and fragments of a synthetic inhibitor, Chem. Pharm. Bull., 38 (1990) 2253–2255.Google Scholar
  40. 40.
    Underwood, D.J., Strader, C.D., Rivero, R., Patchett, A.A., Greenlee, W. and Predergast, K., Structural model of antagonist and agonist binding to the angiotensin II, AT 1 subtype, G protein coupled receptor, Chem. Biol., 1 (1994) 211–221.Google Scholar
  41. 41.
    Aquino, C.J., Armour, D.R., Bermann, J.M., Birkemo, L.S., Carr, R.A.E., Croom, D.K., Dezube, M., Dougherty, Jr., R.W. Ervin, G.N., Grizzle, M.K., Head, J.E., Hirst, G.C., James, M.K., Johnson, M.F., Miller, L.J., Queen, K.L., Rimele, T.J., Smith, D.N. and Sugg, E.E., Discovery of 1,5-Benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity: 1. Optimization of the Agonist’ Trigger’, J. Med. Chem., 39 (1996) 562–569.Google Scholar
  42. 42.
    Hirst, G.C., Queen, K.L., Sugg, E.E. and Willson, T.M., Conversion of acyclic nonpeptide CCK antagonist into CCK agonists, Bioorg. Med. Chem. Lett., 7 (1997) 511–514.Google Scholar
  43. 43.
    Samanen, J., GPVIIb/IIIa antagonists, Ann. Rep. Med. Chem., 31 (1996) 91–100.Google Scholar
  44. 44.
    Engleman, V.W., Kellogg, M.S. and Rogers, T.E., Cell adhesion integrins as pharmaceutical targets, Ann. Rep. Med. Chem., 31 (1996) 191–200.Google Scholar
  45. 45.
    Aumailley, M., Gurrath, M., MÜller, G., Calvete, J., Timpl, R. and Kessler, H., Arg-Gly-Asp constrained within cyclic pentapeptides: Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1, FEBS Lett., 291 (1991) 50–54.Google Scholar
  46. 46.
    Keenan, R., Miller, W., Ali, F., Barton, L., Bondinell, J., Burgess, J., Callahan, J., Calvo, R., Cousins, R., Gowen, M., Huffman, W., Hwang, S., Jakas, D., Ku, T., Kwon, C., Lago, A., Mombouyran, V., Nguyen, T., Ross, S., Samanen, J., Takata, D., Uzinskas, I., Venslavsky, J., Wong, A., Yellin, T. and Yuan, C., Nonpeptide vitronectin receptor antagonists, Abstract MEDI 236, 211th ACS National Meeting, 1996.Google Scholar
  47. 47.
    Ariëns, E.J., Wuis, E.W. and Veringa, E.J., Stereoselectivity of bioactive xenobiotics: A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology, Biochem. Pharmacol., 37 (1988) 9–18.Google Scholar
  48. 48.
    Friedman, L. and Miller, J.G., Odor incongruity and chirality, Science, 172 (1971) 1044–1046.Google Scholar
  49. 49.
    HÖltje, H.-D. and Marrer, S., A molecular graphics study on structure-action relationships of calcium-antagonistic and agonistic 1,4-dihydropyridines, J. Comput.-Aided Mol. Design, 1 (1987) 23–30.Google Scholar
  50. 50.
    Kubinyi, H., QSAR: Hansch analysis and related approaches, VCH, Weinheim, 1993.Google Scholar
  51. 51.
    BÖhm, H.-J., The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure, J. Comput.-Aided Mol. Design, 8 (1994) 243–256.Google Scholar
  52. 52.
    Rum, G. and Herndon, W.C., Molecular similarity concepts: 5. Analysis of steroid-protein binding constants, J. Am. Chem. Soc., 113 (1991) 9055–9060.Google Scholar
  53. 53.
    Good, A.C., Peterson, S.J. and Richards, W.G., QSAR's from similarity matrices: Technique validation and application in the comparison of different similarity evaluation methods, J. Med. Chem., 36 (1993), 2929–2937.Google Scholar
  54. 54.
    Good, A.C., 3D molecular similarity indices and their application in QSAR studies, In: Dean, P. (Ed.) Molecular similarity in drug design, Chapman and Hall, New York, 1995, pp. 24–56.Google Scholar
  55. 55.
    Martin, Y.C., Lin, C.T., Hetti, C. and DeLazzer, J., PLS analysis to detect nonlinear relationships between biological potency and molecular properties, J. Med. Chem., 38 (1995) 3009–3015.Google Scholar
  56. 56.
    Kubinyi, H., A General View on Similarity and QSAR Studies, In Computer-assisted lead finding and optimization, Proceedings of the 11th European Symposium on Quantitative Structure-Activity Relationships, Lausanne, Switzerland, 1996; van der Waterbeemd, H., Testa, B. and Folkers, G. (Eds.); Verlag Helvetica Chimica Acta and VCH: Basel, Weinheim, 1997, pp. 7–28.Google Scholar
  57. 57.
    Klebe, G., Abraham, U. and Mietzner, T., Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological potency, J. Med. Chem., 37 (1994) 4130–4146Google Scholar
  58. 58.
    Kubinyi, H., Hamprecht, F.A. and Mietzner, T., Three-dimensional quantitative similarity-activity relationships (3D QSiAR), from SEAL similarity matrices, manuscript submitted for publication.Google Scholar
  59. 59.
    Kearsley, S.K. and Smith, G.M., An alternative method for the alignment of molecular structures: Maximizing electrostatic and steric overlap, Tetrahedron Comp. Methodol., 3 (1990) 615–633.Google Scholar
  60. 60.
    Klebe, G., Mietzner, T. and Weber, F. Different approaches toward an automatic alignment of drug molecules: application to sterol mimics, thrombin and thermolysin inhibitors, J. Comput.-Aided Mol. Design, 8 (1994) 751–778.Google Scholar
  61. 61.
    Cho, S.J. and Tropsha, A., Cross-validated R 2 guided region selection for comparative molecular field analysis (CoMFA): A simple method to achieve consistent results, J. Med. Chem., 38 (1995) 1060–1066.Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Hugo Kubinyi

There are no affiliations available

Personalised recommendations