Advertisement

Drug-Target Associations Inducing Protein Folding

Chapter
Part of the Soft and Biological Matter book series (SOBIMA)

Abstract

Structure-based drug design has met only modest success due mainly to two reasons: a) as shown in the previous chapter, pharmacologically relevant features are often enshrined in the epistructure, not in the structure itself; and b) the targettable features are often found in structurally floppy regions. In this chapter we shall focus on the latter aspect, first highlighting the inadequacy of standard rational design to deal with it. This is because structural adaptation upon ligand binding resulting in induced folding is usually very difficult to predict. Thus, dynamic information must be incorporated into rational drug design. The conformation of the protein chain in complex with the drug ligand often differs significantly from the conformation of the apo form of the protein, and the structural difference is often unpredictable. In fact, the induced folding problem is every bit as difficult as the protein folding problem, whose arduous solution required a combination of structural and epistructural approaches, as described in Chap.  3. Local conformational plasticity of the protein target is probably the main reason for the modest interest in rational drug design. Thus, floppy regions such as the activation loop or nucleotide-binding loop in a kinase are seldom targeted with small molecule inhibitors in spite of their value as selectivity filters. For example, the activation loop is the structural region that presents the largest amino acid variability within kinase families and thus its compositional uniqueness makes it an attractive target to control specificity. In this chapter we advocate for a strategy to target flexible regions, offering a way to control the induced folding and turn it into a selectivity-promoting feature. Drugs designed to wrap disordered regions in the target may be used to steer induced folding in specific controllable ways, i.e. by inducing the formation of specific dehydrons. The results surveyed in this chapter herald the paradigmatic concept of “wrapping drugs for structurally adaptable targets”. The wrapping-induced folding concept is illustrated by redesigning the anticancer drug imatinib in order to redirect its affinity towards a floppy region in JNK1, which constitutes an important target in the treatment of ovarian cancer. Thus, this chapter reveals that insights from epistructural physics become essential to incorporate conformational dynamics into the technological base of the drug design platforms.

Keywords

Ovarian Cancer Chronic Myeloid Leukemia Activation Loop Packing Defect Rational Drug Design 
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.

References

  1. 1.
    Dancey J, Sausville EA. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov. 2003;2:296–313.CrossRefGoogle Scholar
  2. 2.
    Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol. 2005;45:357–84.CrossRefGoogle Scholar
  3. 3.
    Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science. 2000;289:1938–42.ADSCrossRefGoogle Scholar
  4. 4.
    Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med. 2007;357:258–65.CrossRefGoogle Scholar
  5. 5.
    Crespo A, Fernández A. Kinase packing defects as drug targets. Drug Discov Today. 2007;12:917–23.CrossRefGoogle Scholar
  6. 6.
    Teague S. Implications of protein flexibility for drug discovery. Nat Rev Drug Discov. 2003;2:527–41.CrossRefGoogle Scholar
  7. 7.
    Damm KL, Carlson HA. Exploring experimental sources of multiple protein conformations in structure-based drug design. J Am Chem Soc. 2007;129:8225–35.CrossRefGoogle Scholar
  8. 8.
    Hornak V, Simmerling C. Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov Today. 2007;12:132–8.CrossRefGoogle Scholar
  9. 9.
    Erickson J. Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem. 2004;47:45–55.CrossRefGoogle Scholar
  10. 10.
    Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. Science. 2004;303:1800–5.ADSCrossRefGoogle Scholar
  11. 11.
    Pietrosemoli N, Crespo A, Fernández A. Dehydration propensity of order-disorder intermediate regions in soluble proteins. J Proteome Res. 2007;6:3519–26.CrossRefGoogle Scholar
  12. 12.
    Chen J, Zhang X, Fernández A. Molecular basis for specificity in the druggable kinome: sequence-based analysis. Bioinformatics. 2007;23:563–72.CrossRefGoogle Scholar
  13. 13.
    Fernández A. Keeping dry and crossing membranes. Nat Biotechnol. 2004;22:1081–4.CrossRefGoogle Scholar
  14. 14.
    Fernández A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, Wulf S, Shavrin A, Qin C, Ma J, Trent J, Lin Y, Han HD, Mangala LS, Bankson JA, Gelovani J, Samarel A, Bornmann W, Sood AK, Lopez-Berestein G. An anticancer c-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest. 2007;117:4044–54.CrossRefGoogle Scholar
  15. 15.
    Crunkhorn S. Anticancer drugs: redesigning kinase inhibitors. Nat Rev Drug Discov. 2008;7:120–1.CrossRefGoogle Scholar
  16. 16.
    Fernández A, Sanguino A, Peng Z, Crespo A, Ozturk E, Zhang X, Wang S, Bornmann W, Lopez-Berestein G. Rational drug redesign to overcome drug resistance in cancer therapy: imatinib moving target. Cancer Res. 2007;67:4028–33.CrossRefGoogle Scholar
  17. 17.
    Vivas-Mejia P, Benito JM, Fernández A, Han HD, Mangala L, Rodriguez-Aguayo C, Chavez-Reyes A, Lin YG, Carey MS, Nick AM, Stone RL, Kim HS, Claret FX, Bornmann W, Hennessy BT, Sanguino A, Peng Z, Sood AK, Lopez-Berestein G. c-Jun-NH2-kinase-1 inhibition leads to antitumor activity in ovarian cancer. Clin Cancer Res. 2010;16:184–94.CrossRefGoogle Scholar
  18. 18.
    Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.CrossRefGoogle Scholar
  19. 19.
    Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.CrossRefGoogle Scholar
  20. 20.
    Force T, Krause D, van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332–44.CrossRefGoogle Scholar
  21. 21.
    Demetri GD. Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest. 2007;117:3650–3.CrossRefGoogle Scholar
  22. 22.
    Fernández A, Bazan S, Chen J. Taming the induced folding of drug-targeted kinases. Trends Pharmacol Sci. 2009;30:66–71.CrossRefGoogle Scholar
  23. 23.
    Fernández A, Fraser C, Scott R. Purposely engineered drug-target mismatches for entropy-based drug optimization. Trends Biotechnol. 2012;30:1–7.CrossRefGoogle Scholar
  24. 24.
    Montes de Oca J, Rodriguez Fris A, Appignanesi G, Fernández A. Productive induced metastability in allosteric modulation of kinase function. FEBS J. 2014;281:3079–91.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.National Research Council (CONICET)Buenos AiresArgentina
  2. 2.Rice UniversityHoustonUSA

Personalised recommendations