Theme 6 Lead Optimisation

Question 1

What is a primary assay used for in lead optimization?

Answer 1

To measure potency and selectivity towards a target

It quantifies levels of inhibition by measuring the amount of product.

Question 2

What is a secondary assay used for?

Answer 2

To measure potency and efficacy within a more complex system

For example, assessing activity in a whole cell.

Question 3

What does in vivo optimization identify?

Answer 3

Phenotypic activity and efficacy at a whole system point

For example, effects shown in studies of mice on tissues or organs.

Question 4

Define potency in the context of lead optimization.

Answer 4

Concentration of a compound required to achieve the desired effect

Measured as IC50 or EC50.

Question 5

What is efficacy?

Answer 5

The degree of effect of a compound, represented as a percentage of a standard

This is disease-specific.

Question 6

What does selectivity refer to in drug compounds?

Answer 6

The ability of a compound to act in a specific target activity against other biological targets

Important for assessing overall safety.

Question 7

List the three physical and pharmaceutical properties optimized in lead optimization.

Answer 7

• Lipophilicity
• Solubility
• Permeability

Question 8

What is lipophilicity?

Answer 8

The affinity of a compound for a lipophilic environment

Measured as LogP for neutral molecules and LogD for ionizable molecules.

Question 9

What are typical LogP values for oral drugs?

Answer 9

2-4

For drugs requiring blood-brain barrier penetration, typical values are 3-5.

Question 10

What influences solubility?

Answer 10

Lipophilicity, the ability of a drug to pass through aqueous compartments

Depends on functional groups and physical properties of the solid.

Question 11

What is permeability in drug optimization?

Answer 11

The ability of a drug to permeate a cell membrane and be soluble

Measured using PAMPA and Caco-2 assays.

Question 12

What does the apparent permeability coefficient (Papp) represent?

Answer 12

Permeability at steady state conditions

Calculated using the rate of permeation across cells.

Question 13

What does high oral bioavailability indicate?

Answer 13

A lower dose can be administered, minimizing the risk of off-target effects.

Question 14

Define ligand efficiency.

Answer 14

Assesses and compares compounds based on how they bind to the target

Defined as the free energy of binding averaged for each non-hydrogen atom.

Question 15

What is lipophilic ligand efficiency (LLE)?

Answer 15

A measure of how the lipophilicity of a compound contributes to its potency

Calculated as LLE = pIC50 - logP.

Question 16

What is a desirable LLE value range?

Answer 16

Between 5 and 7

Question 17

What are the issues with very high lipophilicity?

Answer 17

• Poor solubility
• Increased non-specific binding
• Reduced bioavailability

Question 18

What happens if lipophilicity is too low?

Answer 18

The drug may fail to cross the membrane

High solvation reduces permeability through the lipid membrane.

Question 19

What are two key factors that influence aqueous solubility?

Answer 19

• Polarity of the drug molecule
• Crystal lattice energy of the solid crystal form

Question 20

What is crystal lattice energy?

Answer 20

The energy released when ions, atoms, or molecules form a crystalline solid

Also defined as the energy required to break the solid lattice into components.

Question 21

What methods can reduce metabolism?

Answer 21

• Reduce lipophilicity
• Invert stereochemistry
• Modify steric environment
• Alter electronic characteristics
• Introduce conformational constraints

Question 22

What are bioisosteres?

Answer 22

Groups that are near equal in shape and volume and have similar distributions of electrons

They exhibit similar physical properties.

Question 23

What is scaffold hopping?

Answer 23

A subset of bioisosteres where non-pharmacophoric elements are substituted

Used to improve physical or pharmaceutical properties.

Question 24

What is the role of fluorine in medicinal chemistry?

Answer 24

To modify the properties of the lead compound. its addition increases electronegativity and also acts as a hydrogen bond acceptor. It increases lipophilicity and improves permeability across membranes. It increases bioavailability and potency as metabolism at this site is blocked as it cannot be oxidised.

It can drastically change potency and physical & pharmaceutical properties.

Question 25

what does holmologation do to a compound

Answer 25

inc lipophilicity and binding affinity. steric sheilding can increase metabolic stability increasing bioavailability

Question 26

what does conjugation achieve

Answer 26

less rotatable bonds means more rigid structure and less of a change in entropy as there is less disorder. The molecule is already the compatible shape before reaching the active site

Question 27

equation for ligand efficiency

Answer 27

LE = (-1.37/heavy atom count) * LogKd or LE = -deltaG / HAC

kd can be substituted for IC50 or EC50