Lecture 16 Flashcards
Receptor and Drug Interactions
Drug
A drug is a chemical substance that causes a change in a biological system. Many drugs exert their effects by interacting REVERSIBLY with very specific biological molecules called receptors.
Ligands
Drugs in receptor binding studies.
Agonist
A ligand that binds to, and provokes a signal from a receptor via conformational changes in the excited state
Antagonist
A ligand that binds to a receptor and induces no signal. Blocks agonist binding. Little conformational change overall. Can result from a ligand with too strong of a bond to its receptor.
Receptor
A macromolecular component of the organism that binds the drug and initiates its effect.
Induced Fit
- Receptors contain a binding site (hollow or cleft in the receptor surface) that is recognized by the ligand
- Binding of the ligand involves intermolecular bonds
- Binding results in an induced fit of the receptor protein
- Change in receptor shape results in a ‘domino’ effect
- Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell
- It departs the receptor unchanged and is not permanently bound
Bonds + Induced Fit
- Before the induced fit the intermoleculer bonds are not at optimum length for maximum binding strength
- After induced fit, intermoleculer bond lengths are optimized
Balanced Interactions
- Binding needs to be strong enough to hold messenger in place long enough for signal to transduct
- Interaction needs to be weak enough to allow the messenger to depart
- Balance of strong but reversible (usually weak, non-convalent interactions)
Drug-Receptor Interactions (2)
- Irreversible
2. Reversible
Irreversible Interactions
- Usually a covalent bond interaction
- Penicillin is an example that acts as a suicide inhibitor
- Sometimes want this interaction like with penicillin or anti-cancer drugs
Reversible Interactions
- More desired and drug can be excreted eventually
- Multiple weak interactions that are stable together
- Hydrogen bonds, ionic bonds, hydrophobic bonds
Ionic Bonds
- Moderately strong
- Between two opposite charges
- Very common
- Stronger the closer the two charges are (closer the drug is to the receptor)
- Acid bind with bases and bases bind with acids
Hydrogen Bonds
- Diplo-diplo interaction between hydrogen and an electronegative atom (O, N, F)
- Differences in electronegativities lead to partial polarizations
- Greater the difference in electronegativities, the greater the bond strength
- Moderately strong, very common
- Weaker than ionic, stronger than hydrophobic
Hydrophobic Interactions
- Between nonpolar, organic molecules
- AKA Van der Waals or London forces
- Weak
- Hydrophobes interact with itself over forming hydrogen bonds with water
- From transient dipoles induced by neutral, non-polar molecules
Agonist Design
- Agonists mimic the natural messenger of a receptor
- Agonists bind reversibly to the binding site and produce the same induced fit as the natural messenger - receptor is activated
- Similar intermolecular bonds formed as with natural messenger
- Agonists are often similar in structure to the natural messenger
Agonist Requirements (3)
- The agonist must have the correct binding groups
- The binding groups must be correctly positioned to interact with complementary binding regions
- The drug must have the correct shape to fit the binding site
Correct Binding Groups
- Identify important binding interactions in natural messenger
- Agonists are designed to have functional groups capable of same interactions
- Usually require same number of interactions
Correct Positioning of Binding Groups
- Binding groups must be positioned such that they can interact with complementary binding regions at the same time
- One enantiomer of a chiral drug normally binds more effectively than the other
- Different enantiomers likely to have different biological properties
Correct Size and Shape
- Agonist must have correct size and shape to fit binding site
- Groups preventing access are called steric shields or steric blocks
Design of Antagonists
- Antagonists bind to the binding site but fail to produce the correct induced fit - receptor is not activated
- Normal messenger is blocked from binding
- Antagonists can form binding interactions with binding regions
in the binding site not used by the natural messenger.
-Induces a DIFFERENT induced fit from the natural messenger due to its extra interactions
