16- sar part 2 properties Flashcards
what is potency? what are the units of high and low potency?
Measure of the concentration of drug required to achieve an effect
mM and uM are less common (academic) and low potency
nM and pM are most common (industry) and very potent
explain the four steps of SAR to optimize the binding of drugs to biomolecules
- Make structural changes to a molecule
- Measure the potency (effect)
- measure concentration before and after
- Relate the effect to the structural change
- size of substituent? h-bond donor?
- Use this information to design the next compound to test
explain what SPR is
- Make structural changes to a molecule
Measure various properties of the molecule (solubility, melting point etc.)
Relate the effects to the structural change
Use this information to design the next compound to test
what are the three component to make a molecule (drug like)?
potent (Small dose for desired effect) bioavailable (Drug (%) enters blood stream after dosing (oral)) chemical behaviour (Solid, liquid, Stability, Ease of synthesis)
what are the eight common property measurement?
- solubility
- pKa
- LogP or LogD
- molecular weight
- permeability
- melting point
- metabolism
- protein binding
explain the general biological barrier model
as the drug passes from the pill into the location in your body where it needs to work, not all drug molecules will pass each barrier. try to maximize the amount that does pass
explain the stomach environment
- strong acid (pH 1.4 to 2.1)
- Drug must be water soluble
- Drug must survive strong acid
- Very little or no drug is absorbed
- transit time approx 0.5 to 1 hour
explain the intestinal environment
- Mildly acidic to neutral pH (4.4 to 6.8)
- Bile salts
- Form micelles to aid in fat digestion
- Solubilize lipophilic drugs to allow them to dissolve better
- if the drug is too lipophilic they become too attached to the bile salt, causing a problem
- can be good or bad, depends on the nature of the drug
- most drugs are absorbed here
how are most drugs absorbed?
95% by passive diffusion
how do drugs passively diffuse from the intestines to the blood stream?
just randomly move around in the liquid of the intestine they will come into contact with the cells lining the intestine, and if they are soluble enough in the membranes of the cell, they can pass by diffusion from one side to the other
- have to have water solubility to remain active through the intestinal lumen, in the center of the intestinal epithelial cell and blood
- have to have water insolubility or hydrocarbon solubility to pass through the the apical and basolateral lining
explain diffusion across the lipid bilayer
- Interior of lipid (hydrocarbon) bilayer is very non-polar
- Intermolecular interactions primarily Van der Walls type
- need van der walls capabilities in order to pass through the chains
- drug molecule has to be able to interact with non-polar molecule
what do drugs require simultaneously in order to cross the lipid bilayer?
- simultaneous opposite properties
- Water solubility to reach the bilayer
- extremely polar environment
- Lipid solubility (water insolubility) to pass through the layer
- extremely non-polar environment
explain the two opposite chemical environments
- Water
- Very polar medium (solvent)
- Lots of hydrogen bonding and dipole interactions
- Hydrophilic
- Lipophobic
- Hydrocarbons (lipids)
- Very non-polar medium (solvent)
- Van der Walls interactions only
- Lipophilic
- Hydrophobic
explain the structure of membrane phospholipids
- have long chain of 2 fatty acids usually attached to glycerol
- on 3rd OH of the glycerol have a phosphate group with a negative charge
- head group has a positive charge to cancel out the negative charge of the phosphate
explain the different types of charges head groups can have
- positive is most common
- when the head groups do not have positive charges, there will be ions surrounding it with +ve charges able to cancel the negative charges
