Lecture 6: Drug-receptor Energetics Flashcards
Drug Shape
-structurally/chemically complementary to binding pocket of receptor
Hydrophobic interactions determine
binding affinity mostly
Charge-charge interactions and H-bonds determine
specificities
Binding pockets
generally chiral, stereochem important
Chemical Interactions
-covalent
-noncovalent
Covalent interactions
irreversible
Noncovalent interactions
-hydrophobic interaction
-electrostatic interaction
-H bonding
-interaction with aromatic groups
Electrostatic interactions
-charge-charge (coulombic)
-charge-dipole
-dipole-dipole
Interactions with aromatic groups
-pi stacking
-T stacking
-cation-pi interaction
Dynamic Equilibrium
when drug (D) binds to receptor (R) reversibly, D, R, and DR complex in equilibrium
-DR <–> D + R
Dissociation Equilibrium Constant
KD= [D][R]/[DR]
KD
-unit is M
-smaller=stronger binding
Antibody and antigen KD values
10pM - 100nM
Hormone and receptor KD values
0.1nM - 10nM
Drugs and protein target KD values
1nM - 100 nM
Drug lead compounds KD values
100nM - 10 nM
when [D] = KD
50% of receptors are occupied
[DR]/[R]t = 1/2
when [D] < KD
less than half receptors occupied
[DR]/[R]t < 1/2
when [D] > KD
more than half receptors occupied
[DR]/[R]t > 1/2
Binding isotherm
[DR]/[R]t = [D]/(KD+[D])
Gibbs free energy for dissociation
-amount of energy needed to break DR complex under standard condition
SLIDE 7
SLIDE 7
Hydrophobic interactions
-nonpolar groups attraction in water
-minimize area of nonpolar surface (=water more stable)
-most common interaction in protein-ligand complexes
-weak but abundant
Amino acids with hydrophobic side chains
aliphatic: Ala, Val, Leu, Ile, Met, Pro
aromatic: Phe, Trp