Drug Discovery

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Drug Discovery
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Sources of Lead Compounds
A) The Natural World
B) The Synthetic World
C) The Virtual World
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Identification of Lead Compounds
A) Isolation and purification solvent-solvent
extraction chromatography crystallisation
distillation B) Structure determination element
al analysis molecular weight mass
spectrum infra red ultra violet nmr
(1H, 13C, 2D) X-ray crystallography
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Lead Compounds from the Natural World
PLANT EXTRACTS
MORPHINE
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Lead Compounds from the Natural World
PLANT EXTRACTS

• OPIUM - Morphine

• CINCHONA BARK - Quinine

• YEW TREE - Taxol

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Lead Compounds from the Natural World
PLANT EXTRACTS
WILLOW TREE - SALICYLIC ACID
Aspirin
COCA BUSH - COCAINE
Procaine
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Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS
ARTEMISININ
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Lead Compounds from the Natural World
VENOMS AND TOXINS
Teprotide
Captopril (anti-hypertensive)
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Lead Compounds from the Natural World
VENOMS AND TOXINS
Tubocurarine (from curare)
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Lead Compounds from the Natural World
VENOMS AND TOXINS
Tubocurarine (from curare)
Atracurium (Neuromuscular blocker)
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Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
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Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
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Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
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Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL SUBSTRATES FOR ENZYMES
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Lead Compounds from the Synthetic World
PRONTOSIL
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Lead Compounds from the Synthetic World
SULFANILAMIDE
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4.4 Lead Compounds from the Synthetic World
COMBINATORIAL SYNTHESIS
AUTOMATED SYNTHETIC MACHINES
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Lead Compounds from the Synthetic World
COMBINATORIAL SYNTHESIS - PEPTIDE SYNTHESIS
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Lead Compounds - Impact of the human genome
project
The Past
Lead Compound
The Future
Targets
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Lead Compounds - de novo design
X-RAY CRYSTALLOGRAPHY
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Lead Compounds - de novo design
PROTEIN STRUCTURE
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Lead Compounds - de novo design
THYMIDYLATE KINASE INHIBITOR
LEAD COMPOUND
Optimisation
ANTICANCER AGENT
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Design of Lead Compounds using NMR Spectroscopy
NMR SPECTROSCOPY
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Structure Activity Relationships (SAR)
AIM - Identify which functional groups are
important for binding and/or activity
METHOD

• Alter, remove or mask a functional group
• Test the analogue for activity
• Conclusions depend on the method of testing in
  vitro - tests for binding interactions with
  target in vivo - tests for target binding
  interactions and/or pharmacokinetics
• If in vitro activity drops, it implies group is
  important for binding
• If in vivo activity unaffected, it implies group
  is not important

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Structure Activity Relationships (SAR)
NOTES ON ANALOGUES

• Modifications may disrupt binding by electronic /
  steric effects
• Easiest analogues to make are those made from
  lead compound
• Possible modifications may depend on other groups
  present
• Some analogues may have to be made by a full
  synthesis (e.g. replacing an aromatic ring with
  a cyclohexane ring)
• Allows identification of important groups
  involved in binding
• Allows identification of the pharmacophore