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FULL TOOLBOX REQUIRED TO COMPETE
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BIOCHEMICAL APPROACHES TO DRUG DESIGN

• Receptor-based Approach
• structure, kinetics, thermodynamics
• Gene- based Approach
• introduction of gene(s), whole cell(s) or
  macromolecular assembly

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Receptor-based Drug Design
? Structure
Structure of a Receptor
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Receptor-based Drug Design
? Structure
Arg47
Lys114
Lys125
Arg46
Arg129
Asn45
Arg13
Lys11
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Receptor-based Drug Design
? Thermodynamics
-DGO (kcal/mol)
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Receptor-based Drug Design
? Kinetics
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Gene-based Approach
? Gene Therapy
Transfer of a therapeutic gene into the target
tissue and maintenance of the gene function for
an acceptable time
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Gene-based Approach
? Gene Therapy Basic Steps
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Gene-based Approach
? Gene Therapy Basic Steps

• Discover Genes
• Design Replacements
• Deliver to cell / body
• Ensure Incorporation
• Detect Function
• Ensure Stability
• Test Toxicity
• Test long-term effects

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Gene-based Approach
? Gene Therapy Delivering Genes
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? Delivering Genes Viral Gene Delivery
Advantages of using Viruses for Gene Delivery
1. Specific cell-binding and entry
properties 2. Efficient targeting of
the transgene to the nucleus of the cell
3. The ability to avoid intracellular
degradation Types of Viruses Used in Gene
Delivery 1. Retroviral Vectors
RNA based viruses . HIV-1 and HIV-2 families
Good gene expression stable for long term
may integrate into host chromosome
.. Easy to produce 2. Adenovirus
DNA based viruses Second most
commonly used in clinical trials
Commonly infect humans, but not dangerous
do not integrate into host chromosome 3.
Herpes Simplex Viruses DNA based virus
Extrachromosomal DNA Ability
to establish long-lived asymptomatic infections
in neurons
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? Delivering Genes NON-Viral Gene Delivery
Advantages of using NON-Viral Gene 1.
No danger of deleterious effects of viruses
2. Reduced immune response Types of
Viruses Used in Gene Delivery 1. Liposomes
Two lipid species, a cationic amphiphile
and a neutral phospholipid High
affinity for plasma membranes and DNA 2.
DNA-ligand conjugates Two components
a DNA binding domain and a ligand for cell
surface Cell targeting is possible
3. Naked DNA Purified DNA . Simplest
approach low transfection efficiency 4.
Ballistic Gene Delivery Physical method
of using microcarriers (Gold particles) coated
with DNA . Uses a gene gun low
efficiency method 5. Calcium phosphate
precipitation method
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? Delivering Genes Cells