1Drug discovery
By serendipity: chance observation
By screening or designing molecules with desired properties
2serendipity and examples
chance observation
a. Compound -> physiological effect -> molecular target
b. Ex. penicillin and sildenafil
3screening
a. Molecular target -> compound -> physiological effect
b. Ex. aspirin, lovastatin
4Challenges faced by drug developers
- Drugs must be potent and very specific in what they target
- Need to have suitable properties to reach their target
- Inhibitors compete with substrate for binding sites
5Kd = the dissociation constant
- Measure of the strength of the interaction between the drug and target
- Lower Kd value, the tighter the binding and the higher the affinity
6ADME properties of drug candidates
A: Absorption
D: Distribution
M: Metabolism
E: Excretion
7Lipinski’s rules: poor absorption
MW of drug is greater than 500
- There are more than 5 H-bond donors
- There are more than 10 H-bond acceptors
- The partition coefficient is greater than 5
8Partition coefficient
measures the tendency of molecule to dissolve in membrane.
9Albumin
serves as the carrier for hydrophobic compounds for distribution
- “Molecular taxi” - helps deliver drugs like fluconazole
10Drug Metabolism: body has 2 ways of defending against foreign compounds
- Oxidation: cytochrome p450 enzymes in the liver
- Conjugation: glutathione, glucuronic acid, and sulfate in the liver
11Conjugation
glutathione, glucuronic acid, and sulfate in the liver
- Highly charged, and polar causing the drug to become more soluble to remove
them from the body
12Drug may be toxic: as seen in acetaminophen
- First step is toxic!
- Conjugation helps remove toxicity
13Sildenafil: case of drug development by serendipity -> increased smooth muscle relaxation
cGMP analog: causes muscle relaxation
- cGMP produced from GTP by guanylate cyclase
- Potent inhibitor of Phosphodiesterase 5
14Aspirin: very important painkiller
- Irreversible inhibitor of COX
15The development of drugs proceeds through several stages
1. Phase 1: volunteers that check for safety
2. Phase 2: real patients that check for safety, efficacy, and dosage
3. Phase 3: thousands of patients and check for safety, efficacy, and side effects
16Proteins are the most versatile macromolecules
- Properties of proteins depends on physical interaction with other molecules
17Three ways in which two proteins bind to each other
Kinase/Substrate: surface and string
Helix-Helix: 2 alpha helices coil and create a coiled structure
- Common in DNA proteins
Surface-Surface: most common way of protein binding
18Affinity purification followed by mass spectrometry
1. Express affinity tagged protein of interest
2. Form protein complex with partners
3. Capture using affinity column
4. Separate via SDS page
5. Reveal identity of each band on SDS-PAGE by mass spectrometry
19What did jellyfish contribute to science?
Fluorophore can be excited using a light at a given wavelength and emit light at a longer
wavelength
- Ex. can excite a blue light (lower wavelength), to emit a yellow light (higher
wavelength)
20FRET
Fluorescence Resonance Energy Transfer
- Very sensitive to distance, the two fluorophores needs to be within 50 angstroms