BMP: Drug Design 6

Question 1

What is chemical space?

Answer 1

A huge collection of chemical structures e.g. heterocycles, carbohydrates, steriods which could potentially be used as drugs

Question 2

What physiochemical property has the biggest effect on ADME of a drug?

Answer 2

Lipophillicity

Question 3

What does lipophillicty effect?

Answer 3

• Solubility
• Absorption
• Plasma protein binding
• Metabolic clearance
• Volume of distribution
• Enzyme/ receptor binding
• Bilary and renal clearance
• CNS penetration
• Storage in tissues
• BA
• Toxicity

Question 4

How does lipophilicty effect solubility

Answer 4

• Solubility decreases with increasing lipophilicity. This leads to formulation issues. However if it is used in topical creams it is more likley to penetrate the skin

Question 5

How does plasma protein binding effect drugs?

Answer 5

Plasma proteins e.g. serum albumin are found in the blood. If the drug binds to the PP then it cannot interact with the receptor and exert its effect

Question 6

What is BA

Answer 6

The balance between solubility and PP binding. Needs to be freely available to interact

Question 7

What is the hydrophobic effect?

Answer 7

The tendency of non-polar substances to aggregate in an aqueous solution and exclude water. This disturbs the water molecules and gives fewer, but stronger water-to-water H-bonds clsoe to the non-polar surface (thereforee water molecules close tonon-olar surface more organised so lower entropy)

Question 8

What is partition coefficnet?

Answer 8

The relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisatiion

xoctonal <-(P)–> xaqueous

P = [X] octonal/ [X]Aqueous

Question 9

Why is 1-octanol frequently used in the lipid phase?

Answer 9

• It is immiscible with water
• Has polar and non-polar regions (Like membrane phospholipids)
• Po/w is fairly easy to measure
• Po/w often correlates well with many biological properties
• It can be predicieted fairly accurately using computational models

Question 10

What is the acidity constant?

Answer 10

Defines the equilibrium between unionised and ionised forms (Ka or pKa = -logKa)

Question 11

1. What is the generic equibrium for an acid and base.
2. Their Acidity constant equations
3. Their %ionisation equations

Answer 11

1. Acid: AH <—> A- + H+
2. Base: B + H+ <—> BH+
3. Ka=[AH]/[A-}[H+]
4. Ka=[BH+]/[B]{H+]
5. %ionised = 100/ 1 + AL^pKa-pH
6. %ionised = 100/1 + ALpH-pKa

Question 12

What does pKa equal?

Answer 12

The pH at which the acid or base is 50% ionised

Question 13

Sulphonamides are acidic. The active form is an anion. What will happen between pH 7-11 and pH 3-7

Answer 13

Between pH 7-11 potency increases as the anion is present. Below these pHs only the neutral form is fomred.

Delocalisation of the conjugate base occurs

Question 14

What is the distibution constant?

Answer 14

The effective lipophilicy to a compound at a given pH and is a function of both the lipophillicty of the unionised compound and the degree of ionisation

Question 15

How is D calculated for an acid or base?

Answer 15

HA — A- + H+

D = [HA]octanol/ [HA]aq + [H]aq

BH+ — B + H+

D = [B[octanol/ [B]aq + [BH+]aq

Question 16

What is required for H=bonding to occur

Answer 16

Correct orrientation for H-bond to be stron - must be along the equator

Question 17

1. What does a goof HBD functional group need?
2. What does a good HBA functional group need?

Answer 17

1. To be highly polarised bond between H atom and EN atom (heteroato). The more polarised the bond, the stronger the H-bond will be
2. A lone pair that can be easily donated. if close to nuclues weaker bond

Question 18

Why are quaternary ammonium salts good HBDs?

Answer 18

They are electron deficnet. These type of groups have a stronger attration for their electrons and therefore decrease the strength of the N-H bond making the proton more electron poor. This result in better HBD

Question 19

Can intermolecular bonds between small molecules be formed in water?

INtramolecular?

Answer 19

Virtually impossible as both the donar and acceptor must first break their bonds with water

these are readily formed - entropically favourable

Question 20

How are the majority of drugs absorbe?

Answer 20

Passive diffusion through the GUT wall

Question 21

What is important for de-solvation?

What are the exceptions

Answer 21

Not too many HBA/D in drug molecule as desolvation and formation of a neutral molecule is unfavourable if the compound forms many H-bonds with water. The dru wont be abel to get through the gut to the blood

ExCPT sugars

Question 22

How can size weight be investigated?

Answer 22

• Molcular weight
• e- density
• polar SA
• Van der Waals SA

Question 23

What are Lipinskis rules of 5?

Answer 23

• Mwt = ,500 Daltones (g/mol)
• Log P < 5
• <10 HBA
• < 5 HBD

Question 24

What are exceptions to LR5

Answer 24

• Atorvastatin - MWT
• Bexarotene - Log P