Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online

CHAPTER 5 - BINDING

E:   MODERN METHODS IN DRUG DEVELOPMENT

BIOCHEMISTRY - DR. JAKUBOWSKI

Last Updated: 03/31/16

Learning Goals/Objectives for Chapter 5E:  After class and this reading, students will be able to

  • describe the basis for the following methods used to design drugs:
    1. combinatorial drug development
    2. computer-aided design
    3. in situ click chemistry
  • describe drugs that target specific
    1. proteins
    2. DNA
    3. RNA
  • describe the benefit of drugs that
    1. are mutivalent
    2. perturb equilibrium

E11.  Links and References

DrugBank from the University of Alberta

DrugBank:  database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information

MOAD:  Mother of All Databases - largest collection of well resolved protein crystal structures with clearly identified biologically relevant ligands annotated with experimentally determined binding data
extracted from literature

References

  1. Moellering, R. et al. Direct inhibition of the NOTCH transcription factor complex. Nature 462,  171 and 182 (2009)
  2. Keiser, M. et al. Predicting new molecular targets for known drugs. Nature 462, 167 and 175 (2009)
  3. Oh, P. et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy.  Nature. 429, pg 629 (2004)
  4. Dumoulin, M. et al. A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature, 424, pg 783 (2003).
  5. Huang, D. et al. Crystal structure of NF-κB (p50)2 complexed to a high affinity RNA aptamer. Proc. Natl. Acad. Sci. USA. 100, pg 9268 (2003)
  6. Sanchez, I. et al. Pivotal Role of oligomerization in expanced polyglutamine neurodegenerative disorders.  Nature. 421, pg 373, (2003)
  7. Hammarstrom, P. et al. Prevention of Transthyretin Amyloid Disease by changing protein misfolding energetics.  Science. 299, pg 713 (2003)
  8. Rusconi, C. et al. RNA apatmaers as reversible antagonists of coagulation factor IXA.  Nature. 419, pg 90, 23 (2002)
  9. Zasloff. Antimicorbial peptides of multicellular organisms.  Nature. 415, pg 389 (2002)
  10. RNA Interference: The Short Answer (blocking mRNA). Nature. 411 pg 428 (2001)
  11. Fernandez-Lopez et al. Rings of Destruction. (Cyclic peptides as drugs). Natuare. 412 pg 392,  452 (2001)
  12. Small but mighty timekeepers.  (small RNA inhibition of translation) Nautre. 408, pg 37 (2000)
  13. Shokat et al. A Chemistry Set for Life.  (Chemical genetics:  inhibitors designed for specific gene products)*** Nature 407, pg 282, 395 (2000)
  14. Clark et al. Molecular Switches in Metastasis.  Nature. 406. pg 466, 532 (2000)
  15. Root et al. Protein Design of an HIV-1 Entry Inhibitor.  Science. 291, pg 884 (2001)
  16. Tyler et al. Peptide nucleic acids targeted to the neurotensin receptor and administered i.p. cross the blood-brain barrier and specifically reduce gene expression .  PNAS, Vol. 96, Issue 12, 7053-7058, June 8, 1999.  
  17. Interfering with Gene Expression (silencing at the mRNA level).  Science. 288, pg 1370 (2000)
  18. Gellman et al. Slaying Bacteria with β-peptides.  Nature. 404, pg 565 (2000)
  19. RNA interference (RNAi by short RNAs that demonstrate transcriptional silencing). Science. 287, pg 2431, 2494 (2000)
  20. Evans and Relling. Pharmocogenomics: Translating function genomics into rational therapeutics. Science. 286, pg 487 (1999)
  21. Kiessling, L et al. Synthetic multivalent ligands in the exploration of cell-surface Current Opinion in Chemical Biology, 4, pg696 (2000)

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