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
Charge-charge interactions (coulombic)
-attraction between + and - charges
-long distance compared to H bonding and hydrophobic interaction
Amino acids that may be cationic at normal pH
Lys
Arg
His
Amino acids that may be anionic at normal pH
Asp
Glu
Cys
dipole interactions
-water is a dipole
-attraction to momentary charge
dipoles in proteins
backbone amide
a-helix (macrodipole
Hydrogen bonds
-between electronegative atoms with H in the middle
-O and N
-shorter than charge-charge
-orientation requires overlapping of orbitals
-ionic ones stronger than neutral
Aromatic rings
quadrupoles
interactions with aromatic rings
-between electron-rich region and electron-deficient region
-pi stacking, T stacking, cation-pi interaction
electron rich regions
-faces of rings
-due to pi electrons
electron deficient regions
-edges of rings
-due to hydrogens
electron distribution
can be shifted by electron withdrawing/donating groups
pi stacking
-parallel stacking of aromatic rings
-stacking in DNA double helix
-sandwich
T stacking
-edge to face interaction
-T shaped
cation-pi interaction
-between + charge and aromatic ring
-parallel-displaced
B-adrenergic receptor
-seven-helix integral membrane protein
epinephrine
agonist for B-adrenergic receptor
Binding of epinephrine to B-adrenergic receptor
Slide 15-16
