Lecture 6: Drug-receptor Energetics Flashcards

1
Q

Drug Shape

A

-structurally/chemically complementary to binding pocket of receptor

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2
Q

Hydrophobic interactions determine

A

binding affinity mostly

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3
Q

Charge-charge interactions and H-bonds determine

A

specificities

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4
Q

Binding pockets

A

generally chiral, stereochem important

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5
Q

Chemical Interactions

A

-covalent
-noncovalent

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6
Q

Covalent interactions

A

irreversible

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7
Q

Noncovalent interactions

A

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

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8
Q

Electrostatic interactions

A

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

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9
Q

Interactions with aromatic groups

A

-pi stacking
-T stacking
-cation-pi interaction

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10
Q

Dynamic Equilibrium

A

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

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11
Q

Dissociation Equilibrium Constant

A

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

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12
Q

KD

A

-unit is M
-smaller=stronger binding

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13
Q

Antibody and antigen KD values

A

10pM - 100nM

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14
Q

Hormone and receptor KD values

A

0.1nM - 10nM

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15
Q

Drugs and protein target KD values

A

1nM - 100 nM

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16
Q

Drug lead compounds KD values

A

100nM - 10 nM

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17
Q

when [D] = KD

A

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

18
Q

when [D] < KD

A

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

19
Q

when [D] > KD

A

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

20
Q

Binding isotherm

A

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

21
Q

Gibbs free energy for dissociation

A

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

22
Q

SLIDE 7

23
Q

Hydrophobic interactions

A

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

24
Q

Amino acids with hydrophobic side chains

A

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

25
Charge-charge interactions (coulombic)
-attraction between + and - charges -long distance compared to H bonding and hydrophobic interaction
26
Amino acids that may be cationic at normal pH
Lys Arg His
27
Amino acids that may be anionic at normal pH
Asp Glu Cys
28
dipole interactions
-water is a dipole -attraction to momentary charge
29
dipoles in proteins
backbone amide a-helix (macrodipole
30
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
31
Aromatic rings
quadrupoles
32
interactions with aromatic rings
-between electron-rich region and electron-deficient region -pi stacking, T stacking, cation-pi interaction
33
electron rich regions
-faces of rings -due to pi electrons
34
electron deficient regions
-edges of rings -due to hydrogens
35
electron distribution
can be shifted by electron withdrawing/donating groups
36
pi stacking
-parallel stacking of aromatic rings -stacking in DNA double helix -sandwich
37
T stacking
-edge to face interaction -T shaped
38
cation-pi interaction
-between + charge and aromatic ring -parallel-displaced
39
B-adrenergic receptor
-seven-helix integral membrane protein
40
epinephrine
agonist for B-adrenergic receptor
41
Binding of epinephrine to B-adrenergic receptor
Slide 15-16