Theme 6 Lecture 21 Flashcards
bio and BA
What is the goal of lead optimisation in medicinal chemistry?
The goal is to modify a lead compounds molecular structure to improve proeprties such as bioavailability and binding affinity.
dst
What role do rules and metrics play in lead optimisation?
Guide the process by improving the design>synthesis>test cycle thus enhancing affinity.
ratio MW
How is ligand efficiency (LE) defined?
LE measures how efficiently a compound binds to its target.
This is based on the ratio of molecular weight to affinity
5-7
What does lipophilic ligand efficiency (LLE) measure?
How a compounds lipophilicity contributes to its potency with a desirable value of drugs being orally bioavailable between 5-7
What is lipinskis rule of 5.
Predicts good absorption and permeation based on molecular properties like MW and HBA/HBDS.
What does a higher Ligand Efficiency (LE) number indicate for a drug compound?
They could have the same IC50 values, however a different HAC could effect this, so the higher the LE means the better the binding of the drug to its target.
How do rotatable bonds affect a drug’s bioavailability?
Drugs with fewer RBs have higher bioavailabilty because they are more rigid which reduces entropy loss when binding with their target.
Sol,non-s,met,tar
What are the consequences of a drug molecule being too lipophilic?
Poor solubility
Bind non specifically to Plasma proteins
Metabolised more easily
Difficulty reaching the biological target.
balance
What does a LogP value of ~3 indicate in terms of a drug’s bioavailability and target access?
Balance between hydrophilicity and lipophiliccity which means good bioavailability.
What are the disadvantages of having too low or too high LogP values in drug molecules?
Low-unable to penetrate lipid membrane=poor absorbtion
High- diffiuclty in dissolving in aq GI tract leading to poor absorbtion
what entropy changes occur when hydrogen bonds between a drug and water molecules are broken?
Breaking hydrogen bonds with the drug leads do increase in entropy as the water molecules are disordered
How does entropy contribute to the partitioning of a drug into the lipid membrane?
When the drug forms stronger interactions with the mebrane H-bonds with water are broken, thus the reaction becomes enrgetically favourable due to water entering the bulk phase, the energy needed to break the bonds
This causes a negative delta G which is energetcically favourable
