Protein-Ligand Interactions as the Basis for Drug Action

  • Gerhard Klebe
Conference paper
Part of the NATO Science for Peace and Security Series A: Chemistry and Biology book series (NAPSA)


Lead optimization seeks for conclusive parameters beyond affinity to profile drug-receptor binding. One option is to use thermodynamic signatures since different targets require different mode-of-action mechanisms. Since thermodynamic properties are influenced by multiple factors such as interactions, desolvation, residual mobility, dynamics, or local water structure, careful analysis is essential to define the reference point why a particular signature is given and how it can subsequently be optimized. Relative comparisons of congeneric ligand pairs along with access to structural information allow factorizing a thermodynamic signature into individual contributions.


Gibbs Free Energy Isothermal Titration Calorimetry Residual Mobility Free Energy Contribution Thermodynamic Profile 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Mayr LM, Bojanic D (2009) Novel trends in high-throughput screening. Curr Opin Pharmacol 9:580–588CrossRefPubMedGoogle Scholar
  2. 2.
    Klebe G (2006) Virtual ligand screening: strategies, perspectives, and limitations. Drug Discov Today 11:580–594CrossRefPubMedGoogle Scholar
  3. 3.
    Wermuth CG (2003) Chapter 18: application of strategies for primary structure-activity relationship exploration. In: Wermuth CG (ed) The practice of medicinal chemistry. Elsevier, AmsterdamGoogle Scholar
  4. 4.
    Blundell TL, Jhoti H, Abell C (2002) High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 2:45–53CrossRefGoogle Scholar
  5. 5.
    Kloe GE, de Bailey D, Leurs R, Esch IJP (2009) Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discov Today 14:630–646CrossRefPubMedGoogle Scholar
  6. 6.
    Ajay, Murcko MA (1995) Computational methods to predict binding free energy in ligand-receptor complexes. J Med Chem 38:4953–4967CrossRefPubMedGoogle Scholar
  7. 7.
    Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108CrossRefPubMedGoogle Scholar
  8. 8.
    Klebe G (2013) Drug design, Chapter 4, Springer Reference, Heidelberg, New York, Dordrecht, LondonGoogle Scholar
  9. 9.
    Chaires JB (2008) Calorimetry and thermodynamics in drug design. Annu Rev Biophys 37:135–151CrossRefPubMedGoogle Scholar
  10. 10.
    Murray CW, Verdonk ML (2002) The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J Comput Aided Mol Des 16:741–753CrossRefPubMedGoogle Scholar
  11. 11.
    Nazare M, Matter H, Will DW, Wagner M, Urmann M, Czech J, Schreuder H, Bauer A, Ritter K, Wehner V (2012) Fragment deconstruction of small, potent factor Xa inhibitors: exploring the superadditivity energetic of fragment linking in protein-ligand complexes. Angew Chem Int Ed 51:905–911CrossRefGoogle Scholar
  12. 12.
    Borsi V, Calderone V, Fragai M, Luchinat C, Sarti N (2010) Entropic contribution to the linking coefficient in fragment-based drug design: a case study. J Med Chem 53:4285–4289CrossRefPubMedGoogle Scholar
  13. 13.
    Olsson TSG, Williams MA, Pitt WR, Ladbury JE (2008) The thermodynamics of protein-ligand interactions and solvation: insights for ligand design. J Mol Biol 384:1002–1017CrossRefPubMedGoogle Scholar
  14. 14.
    Ladbury JE, Klebe G, Freire E (2010) Adding calorimetric data to decision making in lead discovery: a hot tip. Nat Rev Drug Discov 9:23–27CrossRefPubMedGoogle Scholar
  15. 15.
    Hann MM, Kerserü GM (2011) Finding the sweet spot: the role of nature and nurture in medicinal chemistry. Nat Rev Drug Discov 11:355–365CrossRefGoogle Scholar
  16. 16.
    Ferenczy GG, Kerserü GM (2010) Thermodynamics guided lead discovery and optimization. Drug Discov Today 15:919–932CrossRefPubMedGoogle Scholar
  17. 17.
    Reynolds CH, Holloway MK (2011) Thermodynamics of ligand binding and efficiency. ACS Med Chem Lett 2:433–437CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Ferenczy GG, Keserü GM (2012) Thermodynamics of fragment binding. J Chem Inf Model 52:1039–1045CrossRefPubMedGoogle Scholar
  19. 19.
    Freire E (2008) Do enthalpy and entropy distinguish first in class from best in class? Drug Discov Today 13:869–874CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Freire E (2009) A thermodynamic approach to the affinity optimization of drug candidates. Chem Biol Drug Des 74:468–472CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Dunitz JD (2003) Win some, lose some: enthalpy-entropy compensation in weak intermolecular interactions. Chem Biol 2:709–712CrossRefGoogle Scholar
  22. 22.
    Weber IT, Agniswamy J (2009) HIV-1 protease: structural perspective on drug resistance. Viruses 1:1110–1136CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Ali A, Bandaranayake RM, Cai Y, King NM, Kolli M, Mittal S, Murzycki JF, Nalam MNL, Nalivaika EA, Özen A, Prabu-Jeyabalan MM, Thayer K, Schiffer CA (2010) Molecular basis for drug resistance in HIV-1 protease. Viruses 2:2509–2535CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Ohtaka H, Freire E (2005) Adaptive inhibitors of the HIV-1 protease. Prog Biophys Mol Biol 88:193–208CrossRefPubMedGoogle Scholar
  25. 25.
    Das K, Lewi PJ, Hughes SH, Arnold E (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88:209–231CrossRefPubMedGoogle Scholar
  26. 26.
    Martin SF, Clements JH (2013) Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes. Annu Rev Biochem 82:267–293CrossRefPubMedGoogle Scholar
  27. 27.
    Steuber H, Heine A, Klebe G (2007) Structural and thermodynamic study on aldose reductase: nitro-substituted inhibitors with strong enthalpic binding contribution. J Mol Biol 368:618–638CrossRefPubMedGoogle Scholar
  28. 28.
    Steuber H, Czodrowski P, Sotriffer CA, Klebe G (2007) Tracing changes in protonation: a prerequisite to factorize thermodynamic data of inhibitor binding to aldose reductase. J Mol Biol 373:1305–1320CrossRefPubMedGoogle Scholar
  29. 29.
    Baum B, Mohamed M, Zayed M, Gerlach C, Heine A, Hangauer D, Klebe G (2009) More than a simple lipophilic contact: a detailed thermodynamic analysis of non-basic residues in the S1 pocket of thrombin. J Mol Biol 390:56–69CrossRefPubMedGoogle Scholar
  30. 30.
    Biela A, Khayat M, Tan H, Kong J, Heine A, Hangauer D, Klebe G (2012) Impact of ligand and protein desolvation on ligand binding to the S1 pocket of thrombin. J Mol Biol 418:350–366CrossRefPubMedGoogle Scholar
  31. 31.
    Biela A, Sielaff F, Terwesten F, Heine A, Steinmetzer T, Klebe G (2012) Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect. J Med Chem 55:6094–6110CrossRefPubMedGoogle Scholar
  32. 32.
    Englert L, Biela A, Zayed M, Heine A, Hangauer D, Klebe G (2010) Displacement of disordered water molecules from the hydrophobic pocket creates enthalpic signature: binding of phosphonamidate to the S1′-pocket of thermolysin. Biochim Biophys Acta 1800:1192–1202CrossRefPubMedGoogle Scholar
  33. 33.
    Homans SW (2007) Water, water everywhere – except where it matters. Drug Discov Today 12:534–539CrossRefPubMedGoogle Scholar
  34. 34.
    Petrova T, Steuber H, Hazemann I, Cousido-Siah A, Mitschler A, Chung R, Oka M, Klebe G, El-Kabbani O, Joachimiak A, Podjarny A (2005) Factorizing selectivity determinants of inhibitor binding toward aldose and aldehyde reductases: structural and thermodynamic properties of the aldose reductase mutant Leu300Pro-fidarestat complex. J Med Chem 48:5659–5665CrossRefPubMedGoogle Scholar
  35. 35.
    Baum B, Muley L, Smolinski M, Heine A, Hangauer D, Klebe G (2010) Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry. J Mol Biol 397:1042–1057CrossRefPubMedGoogle Scholar
  36. 36.
    Muley L, Baum B, Smolinski M, Freindorf M, Heine A, Klebe G, Hangauer D (2010) Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a series of thrombin inhibitors. J Med Chem 53:2126–2135CrossRefPubMedGoogle Scholar
  37. 37.
    Biela A, Betz M, Heine A, Klebe G (2012) Water makes the difference: rearrangement of water solvation layer triggers non-additivity of functional group contributions in protein-ligand binding. ChemMedChem 7:1423–1434CrossRefPubMedGoogle Scholar
  38. 38.
    Biela A, Nasief NN, Betz M, Heine A, Hangauer D, Klebe G (2013) Dissecting the hydrophobic effect on the molecular level: the role of water, enthalpy, and entropy in ligand binding to thermolysin. Angew Chem Int Ed 52:1822–1828CrossRefGoogle Scholar
  39. 39.
    Krimmer S, Betz M, Heine A, Klebe G (2014) Methyl, ethyl, propyl, butyl: futile but not for water, as the correlation of structure and thermodynamic signature shows in a congeneric series of thermolysin inhibitors. ChemMedChem 9:833–846CrossRefPubMedGoogle Scholar
  40. 40.
    Neeb M, Czodrowski P, Heine A, Barandun LJ, Hohn C, Diederich F, Klebe G (2014) Chasing Protons: How ITC, mutagenesis and pKa calculations trace the locus of charge in ligand binding to a tRNA-binding enzyme. J Med Chem 57:5554–5565CrossRefPubMedGoogle Scholar
  41. 41.
    Neeb M, Betz M, Heine A, Barandun LJ, Hohn C, Diederich F, Klebe G (2014) Beyond affinity: enthalpy-entropy factorization unravels complexity of a flat structure-activity relationship for inhibition of tRNA-modifying enzyme. J Med Chem 57:5566–5578CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryUniversity of MarburgMarburgGermany

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