BMP: Drug Design 6 Flashcards
What is chemical space?
A huge collection of chemical structures e.g. heterocycles, carbohydrates, steriods which could potentially be used as drugs
What physiochemical property has the biggest effect on ADME of a drug?
Lipophillicity
What does lipophillicty effect?
- Solubility
- Absorption
- Plasma protein binding
- Metabolic clearance
- Volume of distribution
- Enzyme/ receptor binding
- Bilary and renal clearance
- CNS penetration
- Storage in tissues
- BA
- Toxicity
How does lipophilicty effect solubility
- 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
How does plasma protein binding effect drugs?
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
What is BA
The balance between solubility and PP binding. Needs to be freely available to interact
What is the hydrophobic effect?
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)
What is partition coefficnet?
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
Why is 1-octanol frequently used in the lipid phase?
- 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
What is the acidity constant?
Defines the equilibrium between unionised and ionised forms (Ka or pKa = -logKa)
- What is the generic equibrium for an acid and base.
- Their Acidity constant equations
- Their %ionisation equations
- Acid: AH <—> A- + H+
- Base: B + H+ <—> BH+
- Ka=[AH]/[A-}[H+]
- Ka=[BH+]/[B]{H+]
- %ionised = 100/ 1 + ALpKa-pH
- %ionised = 100/1 + ALpH-pKa
What does pKa equal?
The pH at which the acid or base is 50% ionised
Sulphonamides are acidic. The active form is an anion. What will happen between pH 7-11 and pH 3-7
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
What is the distibution constant?
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
How is D calculated for an acid or base?
HA — A- + H+
D = [HA]octanol/ [HA]aq + [H]aq
BH+ — B + H+
D = [B[octanol/ [B]aq + [BH+]aq
