Lecture 1 Historical Overview of Drug Discovery

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20 Apr 2012
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Lecture 1 PHC320 Historical Overview of Drug Discovery
Chemical substance, affects processes of mind/body
Used in diagnosis, treatment, prevention of disease
Small molecule: synthetic or natural
oBiologicals, antibody, metabolite/anti-metabolite, peptide (hormones)
Drug Discovery
Rational drug design
Isolation of active ingredient
Systematic pharmaceutical target-oriented vs. cell based
History of drug discovery
1. Attacking symptoms
4 humors botanicals
religion contagious concept
spontaneous generation germ theory
Hippocrates medicine
Symptoms attributed to wrong causes
2. Attacking disease (cell-based, systematic drug discovery)
3. Target oriented screening (modern)
Disease definition
1. Microorganism found in abundance in all organisms suffering form the disease,
NOT found in healthy organisms
2. Microorganisms isolated from diseased organism, grown in pure culture
3. Cultured microorganism causes disease when introduced in healthy organism
4. Microorganism reisolated from diseased experimental host, identified as identical to
original specific causative agent
In disease, not healthy
Isolate, culture
Introduced in healthy and causes disease
Reisolated, identified as same as original
Cell based Systematic Drug Discovery
Taxol from yew trees
purification, synthesis (difficult)
insoluble in water, difficult to deliver
discovery purification mass product pharmacokinetics/metabolism
mechanisms of action
Notes on “Paul Erlich’s Magic Bullet Concept”
The biological effect of a chemical compound depends in its chemical composition
and the cell on which it acts
Connects chemistry with biology and medicine
Ehrlich’s magic bullet concept” drugs that go straight to their intended cell-
structural targets
Targeted medicine: efficaciously attack pathogens yet remain harmless in healthy
Ehrlich’s postulate: “we have to learn to aim chemically”
Drug discovery programme optimized biological activity of a lead compound
through systematic chemical modifications, represented the dawn of all
pharmaceutical research
Compound targets single critical oncoprotein in exclusive, highly specific fashion
Antibodies in a way are magic bullets that identify target themselves without
harming organism
Ehrlich envisioned attaching toxins to antibodies to improve their therapeutic
Ehrlich postulated: “to use synthetic chemistry to modify the starting material
chemically in various ways and analyse resulting products for their quality to heal
Spatial diversity of specific target crucial for identifying high affinity drugs
Optimization and feedback form clinical trials keys to discovering magic bullet
Ehrlich’s idea: use combinations of drugs to prevent resistance.