Drug design Flashcards
What is the Henderson-Hasselbalch equation
pH = pKa + log ([A-]/[HA]) -> log([A-]/[HA]) = pH - pKa
Must know the acid-base properties
What is the pKa
The pH at which the ratio of molar ratio of a drug’s acid to its conjugate base is 1:1
Describe the relationships between pH and pKa
- pH > pKa -> decreased [H+] -> increased [conjugate base] formation
- pH < pKa -> increased [H+] -> increased [acid] formation
Describe ionisation of amines
Partial positive - fairly water soluble
Describe ionisation of carboxyl acids
In acidic environment neutral (asprin)
In body negative charge - pH > pKa = more conjugate base
What is a partition coefficient (P)
Drug usually passes through membrane to get to site of action
Drug solubility determined by contribution of polar, charged and neutral functional groups
What will relative solubilities in aqueous & lipid media will affect
Drug bioavailability
Drug transport
Pharmacodynamic properties
How do you calculate the partition coefficient (logP)
Solubility (octanol)/solubility (water)
Describe log P in terms of oral drug delivery
logP too small - decreased drug absorption
logP too great - decreased water solubility, drug dissolution, drug absorption and bioavailability. Increased membrane trapping
What does hydrogen bonding do
Help drugs bind to their receptors
What is lipinski’s rule of 5 for oral drug delivery
- > 5 H-bond donors
- MW > 500
- Log P > 5
- More than 10 H-bond acceptors
- 10 or fewer rotatable bonds (single bond with no ring and not bound to hydrogen)
Describe Kinases bind ATP
Target - cyclin dependent kinase (regulate cell cycle)
Mechanism - kinase activated by protein binding transfers phosphate from ATP to downstream protein
Implications - protein must have at least 2 conformations
Therapeutic applications - inhibition of cell growth (anticancer/immunosuppressant activity)
Drug development challenges - selective inhibition
Describe rational design for potential ligands
Based on orientation of an Adenine scaffold in kinase active site - orientation makes inhibitors selective for different kinases
What is are structure libraries
original use - large libraries - not very successful
Rational use - Smaller, more diverse built around common scaffold - highly complex unlikely to give ‘hit’ - look for simple structures that give modest activity (potential lead compounds)
