Lecture 2: Drug-receptor Interactions

Question 1

Nature of drug receptors

Answer 1

-most are proteins
-regulatory, transport, structural proteins
-enzymes

Question 2

Quantitative Aspects of DR interactions

Answer 2

-determine relationship between dose and effect
-responsibile for selectivity of drug action

Question 3

Selectivity of drug action

Answer 3

-size, shape, charge of drug molecule
-changes in structure can affect receptor binding
-mediate actions of agonists and antagonists

Question 4

Agonist

Answer 4

-drug that binds to receptor and stimulate response

Question 5

antagonist

Answer 5

-drug that binds to receptor without altering receptor function (stimulating response)
-alter interaction of receptor with another drug

Question 6

Assessing DR interactions

Answer 6

1. receptor binding/target engagement
2. Functional Assays

Question 7

receptor binding/target engagement

Answer 7

-use biochemical or biophysical approach to assessing
-typically measures static event not function

Question 8

Functional Assays

Answer 8

-assessing signaling events associated with receptor activity
-ion influx/second messenger/gene regulation/substrate change

Question 9

concentration-effect

Answer 9

-response to low concentrations of drug increase proportionally
-dose increase = response decrease
-certain concentrations reached where response can no longer increase

Question 10

Concentration-Effect Relationship

Answer 10

linear curve or semi log (s curve)

Question 11

10-90 = 3 log rule

Answer 11

SLIDE 36 v important

Question 12

Affinity

Answer 12

-ability of drug to interact with receptor
-Kd
-determinant of potency
-one drug can have different ones for different receptors

Question 13

Kd

Answer 13

-measure affinity
-dissociation constant

Question 14

high affinity

Answer 14

-tight binding
-low Kd value

Question 15

Law of Mass action

Answer 15

-effect of drug directly proportional to amount of DR complex formed

D + R -ka and kd-> DR –> effect

Question 16

rate of association

Answer 16

-Kon[D][R]
-first part of graph increasing until 100% bound

Question 17

rate of dissociation

Answer 17

Koff [DR]
-last part of graph, decrease in % bound

Question 18

equilibrium

Answer 18

Kon[D][R] = Koff[DR]
or [D][R]/[DR] = KD

Question 19

when KD = [D]

Answer 19

-drug occupies half the receptors
[R] = [DR]

Question 20

relationship between occupied receptor B (DR) and [D]

Answer 20

B = (D*Bmax(R total))/(D+KD)

-essentially michaelis menten equation

Question 21

Law of mass action assumptions made

Answer 21

-binding reversible
-D and R only exist as free and bound
-all receptors have same affinity for D and are independent

Question 22

Bmax

Answer 22

total number of receptors on given cell or tissue
-half this value = KD

Question 23

Radio/labeled receptor binding

Answer 23

-fluorescent marker added to ligand
-receptor + ligand and then filtered

Question 24

Saturation binding analysis

Answer 24

-requires labeled ligand
-not useful for HTS
-use of heterologous competition assays for profiling (assumes test drugs compete for same sight as labeled ligand)

Question 25

Heterologous competition binding

Answer 25

receptor + ligand + test and then filter

Question 26

Pharmacological profiling

Answer 26

-IC50
-Ki
-relative affinity

Question 27

IC50

Answer 27

determined from experimental data

Question 28

Ki

Answer 28

-indirect measure of affinity (KD)
-cheng-prusoff equation

Question 29

Cheng-Prusoff equation

Answer 29

Ki = IC50/[1+L/KD]

Question 30

MATH AND GRAPH

Answer 30

GOFIWHEF