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Molecular Interaction Analysis for Discovery of Drugs Targeting Enzymes and for Resolving Biological Function

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Book cover Multifaceted Roles of Crystallography in Modern Drug Discovery

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Abstract

Analysis of molecular interactions using surface plasmon resonance (SPR) biosensor technology has become a powerful tool for discovery of drugs targeting enzymes and resolving biological function. A major advantage of this technology over other methods for interaction analysis is that it can provide the kinetic details of interactions. This is a consequence of the time resolution of the analysis, which allows individual kinetic rate constants as well as affinities to be determined. A less commonly recognized feature of this technology is that it can reveal the characteristics of more complex mechanisms, e.g. involving multiple steps or conformations of the target or ligand, as well as the energetics, thermodynamics and forces involved.

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References

  1. Huberand W, Mueller F (2006) Biomolecular interaction analysis in drug discovery using surface plasmon resonance technology. Curr Pharm Des 12(31):3999–4021

    Article  Google Scholar 

  2. Pröll F, Fechner P, Pröll G (2009) Direct optical detection in fragment-based screening. Anal Bioanal Chem 393(6–7):1557–1562

    Article  PubMed  Google Scholar 

  3. Danielson UH (2009) Integrating surface plasmon resonance biosensor-based interaction kinetic analyses into the lead discovery and optimization process. Future Med Chem 1(8):1399–1414

    Article  CAS  PubMed  Google Scholar 

  4. Danielson UH (2009) Fragment library screening and lead characterization using SPR biosensors. Curr Top Med Chem 9(18):1725–1735

    Article  CAS  PubMed  Google Scholar 

  5. Healthcare GE (2012) Biacore assay handbook. Bio-Sciences AB, Uppsala, Sweden

    Google Scholar 

  6. Rich RL et al (2009) A global benchmark study using affinity-based biosensors. Anal Biochem 386(2):194–216

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Knoll W (1998) Interfaces and thin films as seen by bound electromagnetic waves. Annu Rev Phys Chem 49:569–638

    Article  CAS  PubMed  Google Scholar 

  8. Stenberg E et al (1991) Quantitative determination of surface concentration of protein with surface plasmon resonance using radiolabeled proteins. J Colloid Interface Sci 143(2):513–526

    Article  CAS  Google Scholar 

  9. Malmqvist M (1993) Biospecific interaction analysis using biosensor technology. Nature 361(6408):186–187

    Article  CAS  PubMed  Google Scholar 

  10. Davis TM, Wilson WD (2000) Determination of the refractive index increments of small molecules for correction of surface plasmon resonance data. Anal Biochem 284(2):348–353

    Article  CAS  PubMed  Google Scholar 

  11. Giannetti AM, Koch BD, Browner MF (2008) Surface plasmon resonance based assay for the detection and characterization of promiscuous inhibitors. J Med Chem 51(3):574–580

    Article  CAS  PubMed  Google Scholar 

  12. Önell A, Andersson K (2005) Kinetic determinations of molecular interactions using Biacore–minimum data requirements for efficient experimental design. J Mol Recognit 18(4):307–317

    Article  PubMed  Google Scholar 

  13. Copeland RA, Pompliano DL, Meek TD (2006) Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov 5(9):730–7399

    Article  CAS  PubMed  Google Scholar 

  14. Swinney DC (2009) The role of binding kinetics in therapeutically useful drug action. Curr Opin Drug Discov Dev 12(1):31–39

    CAS  Google Scholar 

  15. Elinder M et al (2009) Screening for NNRTIs with slow dissociation and high affinity for a panel of HIV-1 RT variants. J Biomol Screen 14(4):395–403

    Article  CAS  PubMed  Google Scholar 

  16. Shuman CF, Vrang L, Danielson UH (2004) Improved structure-activity relationship analysis of HIV-1 protease inhibitors using interaction kinetic data. J Med Chem 47(24):5953–5961

    Article  CAS  PubMed  Google Scholar 

  17. Copeland RA (2005) Evaluation of enzyme inhibitors in drug discovery. Wiley, Hoboken

    Google Scholar 

  18. Elinder M et al (2010) Inhibition of resistant HIV-1 by MIV-170, a slowly dissociating non-nucleoside reverse transcriptase inhibitor. Biochem Pharmacol 80(8):1133–1140

    Article  CAS  PubMed  Google Scholar 

  19. Radi M et al (2009) Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. J Med Chem 52(3):840–851

    Article  CAS  PubMed  Google Scholar 

  20. Markgren PO, Hämäläinen M (1998) Danielson UH (1998) Screening of compounds interacting with HIV-1 proteinase using optical biosensor technology. Anal Biochem 265(2):340–350

    Article  CAS  PubMed  Google Scholar 

  21. Markgren PO et al (2002) Relationships between structure and interaction kinetics for HIV-1 protease inhibitors. J Med Chem 45(25):5430–5439

    Article  CAS  PubMed  Google Scholar 

  22. Shuman CF et al (2003) Elucidation of HIV-1 protease resistance by characterization of interaction kinetics between inhibitors and enzyme variants. Antivir Res 58(3):235–242

    Article  CAS  PubMed  Google Scholar 

  23. Backman D, Monod M, Danielson UH (2006) Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap 1, Sap 2, and Sap 3 from Candida albicans. J Biomol Screen 11(2):165–175

    Article  CAS  PubMed  Google Scholar 

  24. Ehrenberg AE et al (2014) Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors. J Enzyme Inhib Med Chem 29:868–876

    Article  CAS  PubMed  Google Scholar 

  25. Shuman CF, Hämäläinen MD, Danielson UH (2004) Kinetic and thermodynamic characterization of HIV-1 protease inhibitors. J Mol Recognit 17(2):106–119

    Article  CAS  PubMed  Google Scholar 

  26. Winquist J et al (2013) Identification of structural-kinetic and structural-thermodynamic relationships for thrombin inhibitors. Biochemistry 52(4):613–626

    Article  CAS  PubMed  Google Scholar 

  27. Biela A et al (2012) Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect. J Med Chem 55(13):6094–6110

    Article  CAS  PubMed  Google Scholar 

  28. Freire E (2008) Do enthalpy and entropy distinguish first in class from best in class? Drug Discov Today 13(19–20):869–874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Gossas T, Danielson UH (2003) Analysis of the pH-dependencies of the association and dissociation kinetics of HIV-1 protease inhibitors. J Mol Recognit 16(4):203–212

    Article  CAS  PubMed  Google Scholar 

  30. Backman D, Danielson UH (2003) Kinetic and mechanistic analysis of the association and dissociation of inhibitors interacting with secreted aspartic acid proteases 1 and 2 from Candida albicans. Biochim Biophys Acta 1646(1–2):184–195

    Article  CAS  PubMed  Google Scholar 

  31. Dominguez JL et al (2012) Experimental and ‘in silico’ analysis of the effect of pH on HIV-1 protease inhibitor affinity: Implications for the charge state of the protein ionogenic groups. Bioorg Med Chem 20(15):4838–4847

    Article  CAS  PubMed  Google Scholar 

  32. Sussman F et al (2012) On the active site protonation state in aspartic proteases: implications for drug design. Curr Pharm Des 19(23):4257–4275

    Article  Google Scholar 

  33. Gossas T et al (2013) The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors – characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors. Med Chem Commun 4(2):432–442

    Article  CAS  Google Scholar 

  34. Poliakov A et al (2007) Mechanistic studies of electrophilic protease inhibitors of full length hepatic C virus (HCV) NS3. J Enzyme Inhib Med Chem 22(2):191–199

    Article  CAS  PubMed  Google Scholar 

  35. Doyle JS et al (2013) Current and emerging antiviral treatments for hepatitis C infection. Br J Clin Pharmacol 75(4):931–943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Liang TJ, Ghany MG (2013) Current and future therapies for hepatitis C virus infection. New Engl J Med 368(20):1907–1917

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Geitmann M, Dahl G, Danielson UH (2011) Mechanistic and kinetic characterization of hepatitis C virus NS3 protein interactions with NS4A and protease inhibitors. J Mol Recognit 24(1):60–70

    Article  CAS  PubMed  Google Scholar 

  38. Llinàs-Brunet M et al (2004) Structure – activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061. J Med Chem 47(7):1605–1608

    Article  PubMed  Google Scholar 

  39. Jiang Y et al (2013) Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of Hepatitis C Virus (HCV) NS3/4A protease. J Med Chem 57:1753–1769

    Article  PubMed  Google Scholar 

  40. Seeger C et al (2012) Kinetic and mechanistic differences in the interactions between caldendrin and calmodulin with AKAP79 suggest different roles in synaptic function. J Mol Recognit 25(10):495–503

    Article  CAS  PubMed  Google Scholar 

  41. Seeger C et al (2012) Histaminergic pharmacology of homo-oligomeric beta3 gamma-aminobutyric acid type A receptors characterized by surface plasmon resonance biosensor technology. Biochem Pharmacol 84(3):341–351

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry - BMC, Uppsala University, Uppsala, Sweden

    U. Helena Danielson

Authors
  1. U. Helena Danielson
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Correspondence to U. Helena Danielson .

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Editors and Affiliations

  1. Structural Chemistry Department, Merck & Co, Inc., Kenilworth, New Jersey, USA

    Giovanna Scapin

  2. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Disha Patel

  3. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Eddy Arnold

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Danielson, U.H. (2015). Molecular Interaction Analysis for Discovery of Drugs Targeting Enzymes and for Resolving Biological Function. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_17

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