Theme 5 Lead Optimisation Flashcards
What is lead optimisation?
An iterative process where the initial biological lead is chemically modified.
What properties are evaluated and improved during lead optimisation?
- Potency
- Selectivity for the target
- Efficacy
- Physical and pharmaceutical properties
- Safety profile
What is the purpose of the initial in vitro assay in lead optimisation?
To assess selectivity and potency.
What does Kd represent in the context of drug-target interactions?
The equilibrium dissociation constant.
What does a smaller Kd value indicate?
Higher affinity of the drug for the target.
What is the Gibbs free energy equation?
ΔG = ΔH – TΔS
What does a negative change in Gibbs free energy indicate?
A spontaneous favourable binding interaction.
What is the goal of lead optimisation in terms of Gibbs free energy?
To make ΔG more negative.
What interactions are maximized to improve drug-target binding?
Specific interactions such as hydrogen bonding.
What does minimising entropy achieve in drug binding?
Reduces randomness and promotes a more rigid structure.
What are the strongest types of drug-target interactions?
Covalent mechanisms.
What is the significance of stereochemistry in drug binding?
Different stereoisomers (enantiomers. diastereoisomer, ci/tras isomers, structural isomers) may have varying specificity and toxicity profiles.
What does SAR stand for in drug development?
Structure-Activity Relationships.
What is the purpose of pairwise modifications in SAR studies?
To link specific modifications to changes in biological activity.
What does the Hammett equation quantify?
The electron-withdrawing or donating ability of substituents.
What does Log P represent in drug properties?
Lipophilicity of neutral molecules.
What is ligand-based drug discovery (LBDD)?
A method that relies on known ligands to develop new drugs without knowing the target structure.
What is the active analogue approach in drug design?
Compares active and inactive molecules to identify pharmacophore features.
What does COMFA analyze in drug design?
The 3D structure of a molecule to relate activity to molecular fields.
What is the primary focus of structure-based drug discovery (SBDD)?
To utilize the 3D structure of the biological target for rational drug design.
What is the main difference between LBDD and SBDD?
LBDD does not require the target structure; SBDD does.
What techniques are typically used in SBDD?
- Docking studies
- Virtual screening
- De Novo design
Fill in the blank: The formation of specific interactions, such as ______, influences changes in enthalpy.
hydrogen bonding.
True or False: Higher Kd values indicate a higher affinity of the drug for the target.
False.
What is the primary input data for ligand-based drug discovery?
Known active ligands and their activity profiles.
What are the key features of ligand-based drug discovery?
- Uses data from active compounds
- Employs QSAR and pharmacophore modeling
- Conducts similarity searches
