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Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Weir, Ron / Stohner, Jürgen

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Volume 79, Issue 2 (Jan 2007)


Preorganization in biological systems: Are conformational constraints worth the energy?

Stephen F. Martin
  • Corresponding author
  • Department of Chemistry and Biochemistry and The Institute of Cellular and Molecular Biology, The University of Texas, Austin, TX 78712, USA
  • Other articles by this author:
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Published Online: 2009-01-01 | DOI: https://doi.org/10.1351/pac200779020193

It is generally assumed that preorganizing a flexible ligand in the three-dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty during complexation. We now provide the first experimental evidence that demonstrates this common belief is not universally true. Indeed, we find that ligand preorganization may be accompanied by an unfavorable entropy of binding, even when the constrained ligand exhibits a higher binding affinity than its flexible control. Thus, the effects that ligand preorganization have upon energetics and structure in protein-ligand interactions must be reevaluated.

Keywords: enzyme inhibitors; ligand preorganization; molecular recognition; protein-ligand interactions; structure; thermodynamics


International Conference on Organic Synthesis (ICOS-16), International Conference on Organic Synthesis, ICOS, Organic Synthesis, 16th, Mérida, Yucatán, México, 2006-06-11–2006-06-15


  • 1.

    , A. Mann. In The Practice of Medicinal Chemistry, 2nd ed., C. G. Wermuth (Ed.), pp. 233-250, Academic Press, London (2003).CrossrefWeb of ScienceGoogle Scholar

  • 2. (a)

    U. Gerhard, M. S. Searle, D. H. Williams. Bioorg. Med. Chem. Lett. 3, 803 (1993) and refs. therein;CrossrefGoogle Scholar

  • 2. (b)

    , A. R. Khan, J. C. Parrish, M. E. Fraser, W. W. Smith, P. A. Bartlett, M. N. G. James. Biochemistry 37, 16839 (1998).CrossrefGoogle Scholar

  • 3. (a)

    , B. P. Morgan, D. R. Holland, B. W. Matthews, P. A. Bartlett. J. Am. Chem. Soc. 116, 3251 (1994);CrossrefGoogle Scholar

  • 3. (b)

    , P. Ettmayer, D. France, J. Gounarides, M. Jarosinski, M. S. Martin, J. M. Rondeau, M. Sabio, S. Topiol, B. Weidmann, M. Zurini, K. W. Bair. J. Med. Chem. 42, 971 (1999);CrossrefGoogle Scholar

  • 3. (c)

    , Y. S. Tsantrizos, G. Bolger, P. Bonneau, D. R. Cameron, N. Goudreau, G. Kukolj, S. R. LaPlante, M. Llinas-Brunet, H. Nar, D. Lamarre. Angew. Chem., Int. Ed. 42, 1356 (2003).CrossrefGoogle Scholar

  • 4.

    , A. Reichelt, S. F. Martin. Acc. Chem. Res. 39, 433 (2006).CrossrefGoogle Scholar

  • 5.

    , M. P. Doyle, R. E. Austin, A. S. Bailey, M. P. Dwyer, A. B. Dyatkin, A. V. Kalinin, M. M. Y. Kwan, S. Liras, C. J. Oalmann, R. J. Pieters, M. N. Protopopova, C. E. Raab, G. H. P. Roos, Q.-L. Zhou, S. F. Martin. J. Am. Chem. Soc. 117, 5763 (1995).CrossrefGoogle Scholar

  • 6.

    , S. F. Martin, R. E. Austin, C. J. Oalmann, W. R. Baker, S. L. Condon, E. deLara, S. H. Rosenberg, K. P. Spina, H. H. Stein, J. Cohen, H. D. Kleinert. J. Med. Chem. 35, 1710 (1992).CrossrefGoogle Scholar

  • 7.

    , S. F. Martin, G. O. Dorsey, T. Gane, M. C. Hillier, H. Kessler, M. Baur, B. Matha, J. W. Erickson, T. N. Bhat, S. Munshi, S. V. Gulnick, I. A. Topol. J. Med. Chem. 41, 1581 (1998).CrossrefGoogle Scholar

  • 8. (a)

    , J. M. Bradshaw, G. Waksman. Adv. Protein Chem. 61, 161 (2002);CrossrefGoogle Scholar

  • 8. (b)

    K. Machida, B. J. Mayer. Biochim. Biophys. Acta 1747, 1 (2005).Google Scholar

  • 9.

    , J. P. Davidson, S. F. Martin. Tetrahedron Lett. 41, 9459 (2000).CrossrefGoogle Scholar

  • 10.

    , H. R. Plake, T. B. Sundberg, A. R. Woodward, S. F. Martin. Tetrahedron Lett. 44, 1571 (2003).CrossrefGoogle Scholar

  • 11.

    , J. P. Davidson, O. Lubman, T. Rose, G. Waksman, S. F. Martin. J. Am. Chem. Soc. 124, 205 (2002).CrossrefGoogle Scholar

  • 12.

    , J. M. Sturtevant. Proc. Natl. Acad. Sci. USA 74, 2236 (1977).CrossrefGoogle Scholar

  • 13.

    , G. Waksman, S. E. Shoelson, N. Pant, D. Cowburn, J. Kuriyan. Cell 72, 779 (1993).CrossrefGoogle Scholar

  • 14.

    , A. P. Benfield, M. G. Teresk, H. R. Plake, J. E. DeLorbe, L. E. Millspaugh, S. F. Martin. Angew. Chem., Int. Ed. 45, 6830 (2006).CrossrefGoogle Scholar

  • 15.

    , P. Nioche, W.-Q. Liu, I. Broutin, F. Charbonnier, M.-T. Latreille, M. Vidal, B. Roques, C. Garbay, A. Ducruix. J. Mol. Biol. 315, 1167 (2002).CrossrefGoogle Scholar

  • 16.

    , D. H. Williams, E. Stephens, D. P. O'Brien, M. Zhou. Angew. Chem., Int. Ed. 43, 6596 (2004).CrossrefGoogle Scholar

  • 17.

    , C.-Y. Yang, R. Wang, S. Wang. J. Med. Chem. 48, 5648 (2005).CrossrefGoogle Scholar

About the article

Published Online: 2009-01-01

Published in Print: 2007-01-01

Citation Information: Pure and Applied Chemistry, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1351/pac200779020193.

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