Theme 6 Lead Optimisation Flashcards
What is a primary assay used for in lead optimization?
To measure potency and selectivity towards a target
It quantifies levels of inhibition by measuring the amount of product.
What is a secondary assay used for?
To measure potency and efficacy within a more complex system
For example, assessing activity in a whole cell.
What does in vivo optimization identify?
Phenotypic activity and efficacy at a whole system point
For example, effects shown in studies of mice on tissues or organs.
Define potency in the context of lead optimization.
Concentration of a compound required to achieve the desired effect
Measured as IC50 or EC50.
What is efficacy?
The degree of effect of a compound, represented as a percentage of a standard
This is disease-specific.
What does selectivity refer to in drug compounds?
The ability of a compound to act in a specific target activity against other biological targets
Important for assessing overall safety.
List the three physical and pharmaceutical properties optimized in lead optimization.
- Lipophilicity
- Solubility
- Permeability
What is lipophilicity?
The affinity of a compound for a lipophilic environment
Measured as LogP for neutral molecules and LogD for ionizable molecules.
What are typical LogP values for oral drugs?
2-4
For drugs requiring blood-brain barrier penetration, typical values are 3-5.
What influences solubility?
Lipophilicity, the ability of a drug to pass through aqueous compartments
Depends on functional groups and physical properties of the solid.
What is permeability in drug optimization?
The ability of a drug to permeate a cell membrane and be soluble
Measured using PAMPA and Caco-2 assays.
What does the apparent permeability coefficient (Papp) represent?
Permeability at steady state conditions
Calculated using the rate of permeation across cells.
What does high oral bioavailability indicate?
A lower dose can be administered, minimizing the risk of off-target effects.
Define ligand efficiency.
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.
What is lipophilic ligand efficiency (LLE)?
A measure of how the lipophilicity of a compound contributes to its potency
Calculated as LLE = pIC50 - logP.
What is a desirable LLE value range?
Between 5 and 7
What are the issues with very high lipophilicity?
- Poor solubility
- Increased non-specific binding
- Reduced bioavailability
What happens if lipophilicity is too low?
The drug may fail to cross the membrane
High solvation reduces permeability through the lipid membrane.
What are two key factors that influence aqueous solubility?
- Polarity of the drug molecule
- Crystal lattice energy of the solid crystal form
What is crystal lattice energy?
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.
What methods can reduce metabolism?
- Reduce lipophilicity
- Invert stereochemistry
- Modify steric environment
- Alter electronic characteristics
- Introduce conformational constraints
What are bioisosteres?
Groups that are near equal in shape and volume and have similar distributions of electrons
They exhibit similar physical properties.
What is scaffold hopping?
A subset of bioisosteres where non-pharmacophoric elements are substituted
Used to improve physical or pharmaceutical properties.
What is the role of fluorine in medicinal chemistry?
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.
what does holmologation do to a compound
inc lipophilicity and binding affinity. steric sheilding can increase metabolic stability increasing bioavailability
what does conjugation achieve
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
equation for ligand efficiency
LE = (-1.37/heavy atom count) * LogKd or LE = -deltaG / HAC
kd can be substituted for IC50 or EC50
