SAR-1

Question 1

SPR

Answer 1

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

Question 2

“drug like” molecule

Answer 2

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)

Question 3

Common property measurements

Answer 3

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

Question 4

Property optimization

Answer 4

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

Question 5

Bioavailable

Answer 5

Drug (%) enters blood stream after dosing (oral)

Question 6

SPR vs SAR

Answer 6

Very similar, but SPR is much more experiments since there’s more properties to account for.

Question 7

General biological barrier model

Answer 7

Not all drug molecules will pass each barrier
Try to maximize the amount that does pass

Question 8

Stomach environment

Answer 8

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

Question 9

Intestinal environment

Answer 9

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

Question 10

What mechanism (think membrane transport) is used for drug absorption?

Answer 10

passive diffusion

Question 11

Diffusion across lipid bilayer

Answer 11

• Interior of lipid (hydrocarbon) bilayer is very non-polar
• Intermolecular interactions primarily Van der Walls type

Question 12

Drugs require simultaneous “opposite” properties

Answer 12

• Water solubility to reach the bilayer
• Lipid solubility (water insolubility) to pass through the layer

Question 13

Solute properties in water

Answer 13

Very polar medium (solvent) – Lots of hydrogen bonding and dipole interactions – Hydrophilic – Lipophobic

Question 14

Solute properties in hydrocarbons

Answer 14

Very non-polar medium (solvent) – Van der Walls interactions only – Lipophilic – Hydrophobic

Question 15

Why do negatively charged drugs have more difficulties?

Answer 15

Due to the proximity of the negatively charged phosphate group attached to the membrane, which in turn repels the negatively charged drug.

Question 16

Most drugs are ionizable

Answer 16

Basic 75 %
– Will be positive at physiological pH
* Acidic 20 %
– Will be negative at physiological pH
Neutral 5%

Question 17

Ionized =

Answer 17

water soluble, lipid insoluble

Question 18

Neutral =

Answer 18

water insoluble, lipid soluble

Question 19

Liver is designed to “_______” our food

Answer 19

detoxify

Foreign molecules are metabolized to be removed from blood

Question 20

metabolism

Answer 20

Convert substance into a less toxic form. Hydrophobic molecules are highly metabolized.

Question 21

Metabolism phase 1

Answer 21

oxidation

Question 22

Metabolism phase 2

Answer 22

conjugation

Question 23

Drugs are transported to the body by blood

Answer 23

• Blood is mostly water
• Lipophilic molecules bind to carrier proteins in the blood – Plasma protein binding
• Blood contains hydrolytic enzymes – Esterases – Proteases

Question 24

Esterases (hydrolytic enzyme)

Answer 24

Add water to ester

Question 25

Protease (hydrolytic enzyme)

Answer 25

Add water to amide

Question 26

ADME

Answer 26

Absorption
Distribution
Metabolism
Excretion

Question 27

Lipinski’s rule of five

Answer 27

• 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

Question 28

Rule of 5

Answer 28

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