SAR-1 Flashcards
SPR
Make structural changes to a molecule
* Measure various properties of the molecule
* Relate the effects to the structural change
* Use this information to design the next compound to test
“drug like” molecule
Potent – Small dose for desired effect
- Bioavailable – Drug (%) enters blood stream after dosing (oral)
- Chemical behaviour – Solid, liquid – Stability – Ease of synthesis (is it easy to make)
Common property measurements
Solubility: water
* pKa: acid/base nature of the drug
* LogP or LogD: ability to cross membranes (lipophilicity)
* Molecular weight: solubility; ability to cross membranes
* Permeability: ability to cross membranes
* Melting point: solubility; manufacture
* Metabolism: amount entering the body; lifetime in the body Protein binding: amount circulating in the body; lifetime inthe body; availability for activity
Property optimization
Before a drug can bind to its target, it must enter the body and reach the target
* The drug must pass through several chemical barriers in the body to reach its target
* The chemical properties of the drug determine how easily it can cross these barriers
* The goal is to get as much of the drug as possible to the target location
* As the drug’s potency is optimized, its properties also need to be optimized
Bioavailable
Drug (%) enters blood stream after dosing (oral)
SPR vs SAR
Very similar, but SPR is much more experiments since there’s more properties to account for.
General biological barrier model
Not all drug molecules will pass each barrier
Try to maximize the amount that does pass
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
Intestinal environment
Mildly acidic to neutral pH
– 4.4 to 6.8
* Bile salts – Form micelles to aid in fat digestion – Solubilize lipophilic drugs
* Most drugs are absorbed here
What mechanism (think membrane transport) is used for drug absorption?
passive diffusion
Diffusion across lipid bilayer
- Interior of lipid (hydrocarbon) bilayer is very non-polar
- Intermolecular interactions primarily Van der Walls type
Drugs require simultaneous “opposite” properties
- Water solubility to reach the bilayer
- Lipid solubility (water insolubility) to pass through the layer
Solute properties in water
Very polar medium (solvent) – Lots of hydrogen bonding and dipole interactions – Hydrophilic – Lipophobic
Solute properties in hydrocarbons
Very non-polar medium (solvent) – Van der Walls interactions only – Lipophilic – Hydrophobic
Why do negatively charged drugs have more difficulties?
Due to the proximity of the negatively charged phosphate group attached to the membrane, which in turn repels the negatively charged drug.
Most drugs are ionizable
Basic 75 %
– Will be positive at physiological pH
* Acidic 20 %
– Will be negative at physiological pH
Neutral 5%
Ionized =
water soluble, lipid insoluble
Neutral =
water insoluble, lipid soluble
Liver is designed to “_______” our food
detoxify
Foreign molecules are metabolized to be removed from blood
metabolism
Convert substance into a less toxic form. Hydrophobic molecules are highly metabolized.
Metabolism phase 1
oxidation
Metabolism phase 2
conjugation
Drugs are transported to the body by blood
- Blood is mostly water
- Lipophilic molecules bind to carrier proteins in the blood – Plasma protein binding
- Blood contains hydrolytic enzymes – Esterases – Proteases
Esterases (hydrolytic enzyme)
Add water to ester
Protease (hydrolytic enzyme)
Add water to amide
ADME
Absorption
Distribution
Metabolism
Excretion
Lipinski’s rule of five
- Rapid way to evaluate drug-like properties
- Predict poor absorption or permeation – Is a “guess”, only way to know is to measure
- Based on computer analysis of World Drug Index
- Fast, no cost, well documented, widely used
Rule of 5
Compounds that meet 2 or more of the following criteria are not likely to be well absorbed into the body:
More that 5 hydrogen bond donors – OH’s + NH’s
More than 10 hydrogen bond acceptors – N’s + O’s
Molecular weight greater than 500
Calculated LogP (CLogP) greater than 5
Or measured LogP (MLogP) > 4.15
