MCB Lec 13

By serendipity: chance observation
By screening or designing molecules with desired properties

chance observation
a. Compound -> physiological effect -> molecular target
b. Ex. penicillin and sildenafil

a. Molecular target -> compound -> physiological effect
b. Ex. aspirin, lovastatin

- 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

- Measure of the strength of the interaction between the drug and target
- Lower Kd value, the tighter the binding and the higher the affinity

A: Absorption
D: Distribution
M: Metabolism
E: Excretion

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

measures the tendency of molecule to dissolve in membrane.

serves as the carrier for hydrophobic compounds for distribution
- “Molecular taxi” - helps deliver drugs like fluconazole

- Oxidation: cytochrome p450 enzymes in the liver
- Conjugation: glutathione, glucuronic acid, and sulfate in the liver

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

- First step is toxic!
- Conjugation helps remove toxicity

cGMP analog: causes muscle relaxation
- cGMP produced from GTP by guanylate cyclase
- Potent inhibitor of Phosphodiesterase 5

- Irreversible inhibitor of COX

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

- Properties of proteins depends on physical interaction with other molecules

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

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

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)

Fluorescence Resonance Energy Transfer
- Very sensitive to distance, the two fluorophores needs to be within 50 angstroms