Lecture 6: Drug-receptor Energetics

Question 1

Drug Shape

Answer 1

-structurally/chemically complementary to binding pocket of receptor

Question 2

Hydrophobic interactions determine

Answer 2

binding affinity mostly

Question 3

Charge-charge interactions and H-bonds determine

Answer 3

specificities

Question 4

Binding pockets

Answer 4

generally chiral, stereochem important

Question 5

Chemical Interactions

Answer 5

-covalent
-noncovalent

Question 6

Covalent interactions

Answer 6

irreversible

Question 7

Noncovalent interactions

Answer 7

-hydrophobic interaction
-electrostatic interaction
-H bonding
-interaction with aromatic groups

Question 8

Electrostatic interactions

Answer 8

-charge-charge (coulombic)
-charge-dipole
-dipole-dipole

Question 9

Interactions with aromatic groups

Answer 9

-pi stacking
-T stacking
-cation-pi interaction

Question 10

Dynamic Equilibrium

Answer 10

when drug (D) binds to receptor (R) reversibly, D, R, and DR complex in equilibrium
-DR <–> D + R

Question 11

Dissociation Equilibrium Constant

Answer 11

KD= [D][R]/[DR]

Question 12

KD

Answer 12

-unit is M
-smaller=stronger binding

Question 13

Antibody and antigen KD values

Answer 13

10pM - 100nM

Question 14

Hormone and receptor KD values

Answer 14

0.1nM - 10nM

Question 15

Drugs and protein target KD values

Answer 15

1nM - 100 nM

Question 16

Drug lead compounds KD values

Answer 16

100nM - 10 nM

Question 17

when [D] = KD

Answer 17

50% of receptors are occupied
[DR]/[R]t = 1/2

Question 18

when [D] < KD

Answer 18

less than half receptors occupied
[DR]/[R]t < 1/2

Question 19

when [D] > KD

Answer 19

more than half receptors occupied
[DR]/[R]t > 1/2

Question 20

Binding isotherm

Answer 20

[DR]/[R]t = [D]/(KD+[D])

Question 21

Gibbs free energy for dissociation

Answer 21

-amount of energy needed to break DR complex under standard condition

Question 22

SLIDE 7

Answer 22

SLIDE 7

Question 23

Hydrophobic interactions

Answer 23

-nonpolar groups attraction in water
-minimize area of nonpolar surface (=water more stable)
-most common interaction in protein-ligand complexes
-weak but abundant

Question 24

Amino acids with hydrophobic side chains

Answer 24

aliphatic: Ala, Val, Leu, Ile, Met, Pro
aromatic: Phe, Trp

Question 25

Charge-charge interactions (coulombic)

Answer 25

-attraction between + and - charges
-long distance compared to H bonding and hydrophobic interaction

Question 26

Amino acids that may be cationic at normal pH

Answer 26

Lys
Arg
His

Question 27

Amino acids that may be anionic at normal pH

Answer 27

Asp
Glu
Cys

Question 28

dipole interactions

Answer 28

-water is a dipole
-attraction to momentary charge

Question 29

dipoles in proteins

Answer 29

backbone amide
a-helix (macrodipole

Question 30

Hydrogen bonds

Answer 30

-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

Question 31

Aromatic rings

Answer 31

quadrupoles

Question 32

interactions with aromatic rings

Answer 32

-between electron-rich region and electron-deficient region
-pi stacking, T stacking, cation-pi interaction

Question 33

electron rich regions

Answer 33

-faces of rings
-due to pi electrons

Question 34

electron deficient regions

Answer 34

-edges of rings
-due to hydrogens

Question 35

electron distribution

Answer 35

can be shifted by electron withdrawing/donating groups

Question 36

pi stacking

Answer 36

-parallel stacking of aromatic rings
-stacking in DNA double helix
-sandwich

Question 37

T stacking

Answer 37

-edge to face interaction
-T shaped

Question 38

cation-pi interaction

Answer 38

-between + charge and aromatic ring
-parallel-displaced

Question 39

B-adrenergic receptor

Answer 39

-seven-helix integral membrane protein

Question 40

epinephrine

Answer 40

agonist for B-adrenergic receptor

Question 41

Binding of epinephrine to B-adrenergic receptor

Answer 41

Slide 15-16