Drug Design (II) Flashcards
How do enzymes catalyse reactions?
They lower the energy required for the substrate to bind
or they stabilize the intermediate state of the reaction
How does a Transition state analogue work?
Mimics the transition state of the molecule and can bind enzymes (typically better than the substrates themselves)
These analogues are chemically more stable than other types of drugs, and possess more “drug-like” properties
Since they are not a substrate of the enzyme, they are not degraded and show promise for drug development
Notable example: Protease
True/False? It’s easy to find a transition state molecule
False
Isosterisation helps but not always effective
How do Purine Nucleoside Phosphorylases work? What modifications were made to them to form PNP transition state analogues and what are the consequences of these modifications? (2)
PNPs are like hydrolases but they use Phosphate
Inhibitors have N instead of O in the ring (allowing it to be protonated at physiological pH), stabilizing the enzyme
N is turned into a C at the base, making the bond a lot more stable/harder to break down
These result in drugs with Picomolar affinity, essentially irreversible until the enzyme is recycled
How is the PNP transition state in humans different from the PNP transition state in pigs?
Slightly longer in pigs, drugs had to be modified accordingly
What is a problem of increasing concern with antibiotics?
Beta lactam drugs are having their ring opened, and bacteria are getting better at it
Amoxicillin is typically administered with clavulanic acid to this but it doesn’t always help
What is the name of the strain of bacteria that confers beta lactamase activity (and thus antibiotic resistance)?
New Deli Metallo-Beta-Lactamase 1 (NDM-1)
No known beta lactamase inhibitors work here
How is NDM-1 being dealt with?
With transition state analogues, isosteres mostly
Why is selectivity an important concern for drug design?
You might want to inhibit a protease
But the human body has many proteases
Nonspecific inhibition can be very dangerous and make your drug inviable
What are 6 ways you can optimize your drug’s specificity?
Using target/decoy strategies:
- Look at charges in binding pocket and charge drug accordingly
- Exploit all available space of target (create steric clash with decoys)*
- Remove interactions in decoy*
- Exploit flexibility of target
- Displace H2O (might be high E,not favorable)
- Beware the decoys might change to accomodate your drug
What is a problem with viruses and why is drug flexibility such a good countermeasure?
They mutate rapidly, often changing their conformation and dislocating drugs
If a drug is flexible it is more capable of withstanding these changes without losing potency
What is a useful way to target viral enzymes?
Design a drug that targets the carbon backbone of a protein rather than the amino acids (AAs might change but backbone cannot)
Describe the substrate enzyme hypothesis
When designing a drug, it may be tempting to create a molecule that fits within the binding pocket and takes up all available space to maximize favorable interactions
However, having a perfectly space-filling drug makes it extremely susceptible to modifications that change the size/shape of the binding pocket
The Substrate enzyme hypothesis is the notion that drugs that stay within the same space filling enzyme ‘envelope’ are more viable than drugs that extend out of the envelope, even if there are more favorable interactions. This is because the substrate envelope can never change in size without modifying the substrate, which by definition cannot happen
