Rational Drug Design

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Rational Drug Design

• Dr Robert Sbaglia

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Curriculum Vitae

• 1994-1998 Bachelor of Science (Honours),
  University of Melbourne
• 1998-2002 Doctor of Philosophy, Centre for
  Drug Design and Development (later IMB),
  University of Queensland Rheumatoid
  Arthritis
• 2000 University of Perugia, Italy
  Alzheimers Disease
• 2003 Postdoctoral Fellowship, University of
  Florence, Italy - Cancer

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Irrational Drug Design?

• High Throughput Screening (HTS)
• Expensive
• Slow
• Hit and Miss
• Natural Products (eg Taxol)
• Not easily synthesised
• Not easily modified

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Taxol
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Rational Drug Design

• Medical Researchers
• Biologists
• Pharmacologists
• Chemists
• Computational chemists
• Bioinformaticians
• Pharmacists

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The Process
Identify disease protein
Identify active site
Determine structure of Protein
Virtual Screening of Drug Candidates
Synthesis of Lead Compounds
Pharmacological Testing
Optimisation
Clinical Trials
Drug
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How Does Drug Design fit into 2008 Chemistry?

• Unit 3, Area of Study 2, Outcome 2
• structure and systematic nomenclature of alkanes,
  alkenes, amines, chloroalkanes, alkanols and
  carboxylic acids up to C10
• common reactions of organic compounds addition
  reactions of alkenes, substitution reactions of
  alkanes and primary chloroalkanes, oxidation of
  primary alkanols, esterfication
• organic reaction pathways including the
  production of esters from alkenes, condensation
  and polymerisation reactions that produce large
  biomolecules
• primary, secondary and tertiary structure of
  proteins and the function of protein catalysts
  (enzymes)
• biochemical fuels including fermentation of
  sugars to produce ethanol
• the structure and bonding of DNA and its
  applications in forensic analysis
• use of proteins as markers for disease
• function of organic molecules in the design and
  synthesis of medicines including the production
  of aspirin from salicylic acid.

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How Does Drug Design fit into 2008 Chemistry?

• Unit 3, Area of Study 1, Outcome 1
• principles and applications of chromatographic
  techniques and interpretation of qualitative and
  quantitative data from thin layer chromatography
  (TLC), high performance liquid chromatography
  (HPLC) and gas chromatography (GC)
• principles and applications of spectroscopic
  techniques and interpretation of qualitative and
  quantitative data from atomic absorption
  spectroscopy (AAS), infrared spectroscopy (IR),
  mass spectroscopy, nuclear magnetic resonance
  spectroscopy (NMR), and visible and ultraviolet
  spectroscopy (visible-UV)
• matching analytical technique/s to a particular
  task.

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Identification of Disease Protein
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Identification of Disease Protein
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Identify Active Site

• Mutagenesis studies
• Express proteins with changes in amino acid
  sequences
• Identify amino acids involved in function

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Identify Active Site
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Structure Determination

• X-ray Crystallography
• Nuclear Magnetic Resonance (NMR)
• Homology Modelling

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Bovine Rhodopsin Crystal Structure
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Structure Determination

• C5a Receptor
• GPCR
• Membrane Bound
• Homology Model

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Virtual Screening

• Known structures of organic compounds
• Libraries of Virtual Compounds
• Programs calculate affinity for protein
• Narrow down to small number of possiblities

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Virtual Screening
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What makes a good drug?

• Compounds can interact through
• Hydrophobic/hydrophilic pockets
• Charge
• Hydrogen bonding
• Lock and Key

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Virtual Screening
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HIV protease
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Synthesis, Testing and Optimisation

• Small changes to lead compounds
• Must consider
• Solubility
• Specificity
• Bioavailablity
• Toxicity
• Cost

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Synthesis, Testing and Optimisation
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Trials

• Animal Model
• Human Trials
• Phase 1 20-80 people
• Phase 2 100-300 people
• Phase 3 1,000 3,000 people
• Phase 4 post-marketing studies

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