4. Target Identification & Validation

Question 1

Drug target

Answer 1

A molecule involved in a medical problem that is acted on by a drug to stop that disease

Ex. Aspirin stops the molecule COX from working Without COX, there is no pain (COX is the drug target)

Question 2

why are Polysaccharides (carbs) bad drug targets?

Answer 2

Toxicity

Question 3

why are lipids bad drug targets?

Answer 3

LOW SPECIFICITY (do not have a specific shape)

Question 4

why are Nucleic acids (DNA & RNA) bad drug targets?

Answer 4

HARD TO FIND POTENT COMPOUNDS (to bind to DNA & RNA sequences)

Question 5

Pharmacology

Answer 5

the science and study of drugs

Question 6

Why are proteins good drug targets?

Answer 6

Most drugs bind to proteins & modify their activity

96% of drug targets are proteins

Question 7

Pharmacokinetics

Answer 7

the fate of a drug in the body
“what the body does to the drug

Question 8

Pharmacodynamics

Answer 8

the biological action of a drug on the body
“what the drug does to the body”
(drug interaction with cellular targets & effect of a drug on ligand-target interaction)

Question 9

Receptor

Answer 9

Biological molecule to which a drug binds in order to produce an effect
(involved in cellular communication)
(Many receptors are cell surface proteins)

Question 10

How do drugs work?

Answer 10

• receptors bind to messengers (ligands)
• relay message to the cell
• cell reacts by functioning differently

(Drug + Messenger/ ligand + receptor—> cell signal/effect)

Question 11

Signal Transduction

Answer 11

Often a “second messenger” mediates signaling inside the cell (Generated by “effector” proteins)

Question 12

Agonist

Answer 12

trigger receptor effect

Question 13

Antagonist

Answer 13

block receptor activity (easier to make)

Question 14

Enzyme

Answer 14

proteins made of amino acids (Active or catalytic site − Lock & key mechanism; induced fit − Substrates bind and undergo chemical reaction) (bacteria enzyme- penicillin)

Question 15

Substrates

Answer 15

Fit into the active site

Question 16

Drug targets

Answer 16

Macromolecules

Question 17

Examples of enzymes

Answer 17

• Pathogen enzymes
  
  • Bacteria enzymes (Penicillin)
  • Virus enzymes
  • Many HIV drugs (Ex. Protease, reverse transcriptase)
    Human enzymes (Viagra -phosphodiesterase inhibitor)

Question 18

Why don’t products (without enzymes) fit well into active sites?

Answer 18

Enzymes changes the shape of substrates slightly (which is Facilitated by amino acid residues of the enzyme) so that substrates fit well into the active site,
HOWEVER
Products do not fit as well into the active site and therefore dissociate spontaneously

Question 19

Dravet syndrome

Answer 19

Hereditary epilepsy

Molecular cause: mutation in the (SCN1A) gene

Question 20

4 Model organisms

Answer 20

1) Budding yeast
2) Zebrafish
3) Roundworm (C.elegans)
4) Fruit fly (Drosophila)

Question 21

Target Validation

Answer 21

does the loss of the potential target protein actually cause disease?

Question 22

Genomics

Answer 22

is the study of all the genes in the (genome and the interactions among them and their environment)

Question 23

Genetics

Answer 23

is the study of single genes in isolation

Question 24

4 Different ways we identify a drug target

Answer 24

1. Data mining
   
   2. Genome wide association studies
   3. Profiling mRNA/protein
      
      4. Familial studies (inherited disease)

Question 25

Gene expression

Answer 25

Your cells contain the same DNA, but the RNA and proteins may be different from one cell to another

MUSIC ANALOGY
- Sometimes the violin is playing (heart genes are being expressed)
- Sometimes the cello is playing (skin genes are being expressed)
- The instruments in the orchestra are the same throughout the music (instruments = DNA)
Some are quiet at a particular time, some are loud/playing (a gene is being expressed)

Question 26

The Human Genome Project (HGP)

Answer 26

Initiated in 1990
Main goals:
1. Determine number of genes coded by the human genome
2. Sequence the entire human genome
3. Store this information in databases freely available to the public

Question 27

3 Examples of single gene genetic diseases

Answer 27

1. Cystic Fibrosis and the CFTR gene
2. Tay Saks
3. Sickle Cell Anemia

Question 28

4 Examples of multiple gene genetic diseases

Answer 28

1. Diabetes
2. Schizophrenia
3. Autism
4. Obesity

Question 29

Single nucleotide polymorphism (SNP)

Answer 29

Substitution of one base for another at a single site (has several different forms)
SNPs= sites of variation in our genomes

Question 30

SNPs can account for differences in…

Answer 30

• Appearance
• Risk for certain diseases
• Response to drugs
  Many SNPs have no apparent effect

Question 31

Yeast % genes similar to human gene & generation time

Answer 31

46%
2h

Question 32

Zebrafish % genes similar to human gene & generation time

Answer 32

> 80%
6-8 weeks

Question 33

Mice % genes similar to human gene & generation time

Answer 33

95-97%
6 weeks

Question 34

Fruit fly % genes similar to human gene & generation time

Answer 34

61%
10 days

Question 35

Why do we use model organisms

Answer 35

• When there are possible target genes, but it’s unclear whether or not the gene’s protein product plays an important role in disease
• At this stage: Target is identified Target is not yet validated (Validate the target in the model organism)