Enzymes as Drug Targets - Sweatman Flashcards
Why enzymes as drug targets? Downside?
HIGHLY SPECIFIC, good for drug specificity
Negative: specificity could be limiting; there are families of enzymes & activities
What are other potential targets for drugs?
proteins (GPCR), nuclear receptors, DNA
Characteristics of enzyme active site
- Small relative to overall structure
- 3D = precision
- Non-covalent: H-bond, electrostatic, hydrophobic, van der Waals
- excludes bulk solevent
What does a pro-drug do? Why?
Uses specific enzyme to transform inactive molecule to active drug in vivo
Why: to limit drug action to specific areas, when structural requirements are of inhibitor are incompatible with oral absorption
Describe drug activity in different species
It is specific
2 effects of mutation to binding site
- Can change binding site’s size, flexibility, & chemical interactions
- Can change affinity for ligands
Does a mutation need to occur at the binding site in order to disrupt the ligand binding?
No
What are flexible drugs?
Drugs that avoid resistance mutations (ex. NNRTI)
Clinical correlate for drug binding affinity
Drug concentration (dose) required to produce a desired effect
Receptor agonist
Speeds up binding process
Receptor antagonist
Slows down binding process
CHART: Two classifications of receptor antagonists
Active site binding antagonists & allosteric antagonists
CHART: Describe allosteric binding antagonists
Can be either reversible or irreversible and are all noncompetitive
CHART: Describe active-site binding antagonists
Can be reversible (competitive) or irreversible (noncompetitive)
CHART: What are the two types of non receptor antagonists?
Chemical antagonists & physiological antagonists
DDIs
Drug-drug interactions. Can be responsible for ADEs in elderly & are increasingly important with aging population
CYP
Family of enzymes that play a very integral role in clinical agents or drug metabolism.
These enzymes essentially catalyze oxidation of organic substances
EM, PM, IM
Extensive metabolizers, poor metabolizers, intermediate metabolizers
What do CYP inducers do?
They allow for the isoenzymes of CYP to be expressed. Enzyme induction results from an agents ability to bind to nuclear receptors
What can reduced drug metabolism lead to?
Toxicity through the inability of the body to eliminate the drug
How does patient drug metabolism play a role in all this?
Optimal activity correlates w patient’s capacity to activate a pro-drug
What is tylenol an example of in excess?
Toxicity to hepatic metabolites
