1. 1 Biological Discovery High Volume Screening Combinatorial Diversity Structure, Design, Informatics Lead Series Biodisposition Toxicity Efficacy Pharmacokinetics IND Lead Discovery Iterative Preclinical Research Process R&D FULL TOOLBOX REQUIRED TO COMPETE

2. 2 BIOCHEMICAL APPROACHES TO DRUG DESIGN Receptor-based Approach structure, kinetics, thermodynamics Gene- based Approach introduction of gene(s), whole cell(s) or macromolecular assembly

3. 3 Receptor-based Drug Design Structure of a Receptor  Structure

4. 4 Receptor-based Drug Design  Structure ____ _ _ _ _ _ _ Arg129 Lys125 Lys114 Arg46 Arg47 Lys11 Arg13 Asn45

5. 5 Receptor-based Drug Design  Thermodynamics  G O (kcal/mol)

6. 6 Receptor-based Drug Design  Kinetics P + L P:L P*:L k1k1 k -1 k2k2 k -2

7. 7 Gene-based Approach  Gene Therapy Transfer of a therapeutic gene into the target tissue and maintenance of the gene function for an acceptable time

8. 8 Gene-based Approach  Gene Therapy – Basic Steps

9. 9 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

10. 10 Gene-based Approach  Gene Therapy – Delivering Genes

11. 11  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

12. 12  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

13. 13  Delivering Genes – Cells