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Flashcards in Structure Activity Relationships Deck (66):
1

What are the five stages of hit to lead drug discovery?

screening of compound libraries, hits, optimized leads, IND candidates, candidate drugs

2

What kind of binding affinity would a "hit" have?

1-20 um

3

what kind of binding affinity would an optimized lead have?

0.1 -1 um

4

what kind of binding affinity would an IND candidate have?

0.01 um

5

In lead based drug design, the structure of the binding site _______ and compounds/ligands _____

is not known/ are known

6

lead - based drug design can lead to a model of the binding site via

Structure activity relationship studies

7

If you have no protein target crystal structure and no ligand or lead compound...

use high-throughput screeing to identify lead and crystalize protein

8

if you have a protein target crystal structure but no ligand or lead compound...

use de novo drug design - design lead compound based on binding pocket

9

if you have a ligand or lead compound but no protein target crystal structure...

use lead based drug design - rational design of improved compounds

10

if you have ligand or lead compound and protein target crystal structure...

use structure based drug design to design new compounds based on binding site interactions

11

define pharmacophore

basic molecular structure of the lead compound that represents the functional groups required for activity and their spatial orientations relative to each other

12

auxophore:

non-essential portion of a drug that supports the pharmacophore and can be modified to improve drug-like properties

13

the 2D pharmacophore - __________ are important

functional groups

14

3D pharmacophore - __________ is important

spatial orientation of groups

15

how do you evaluate the activity of new analogues during SAR development?

in vitro assays

16

to determine how strucutral modifications affect biological activity against target during SAR development...

determine IC50 or EC50 values for each analogue

17

IC50

half maximal inhibitory concentration

18

EC50

half maximal effective concentration

19

bioisoters for SAR:

atoms or functional groups that share one or more chemical/ physical characteristics and are very different in others

20

characteristics to compare between bioisoters for SAR

size, shape, h-bonding, electronic

21

bioisoters are used in SAR to

identify the effects of size, shape, h-bonding, electronic differences at a single location of the lead compound

22

H and F are bioisoters because they are the same in _____ and different in ____

size/ h-bonding and electronically

23

F and Cl are bioisoters because they are the same in ______ but different in __

h-bonding and electronically/ size

24

NH2 and CH3 are bioisoters because they are the same in ____ and different in ____

size/ hydrogen bonding

25

what are some ways to optimize spatial orientation when optimizing target interactions?

modify 3D location of functional groups, rigidification and conformational blockers

26

addition of functional groups can enhance __________ interactions

hydrophobic or ionic

27

inductive effects

refer to electronic effects of an atom or functional group that is contributed through a single bond

28

inductive effects are primarily a function of

electronegativity

29

resonance effects

sharing of electrons between more than two atoms through delocalization of electrons across a pi-system

30

Functional Group modifications on aromatics can alter _____ of _________

acidity or basicity/ other FGs on aromatic ring

31

resonance effects of FG modifications on aromatics:

structures are stabilized through resonance structures (pi system)

32

Inductive effect of -NR3+, -NH3+

electron withdrawing

33

inductive effect of -COOH, -COOR

electron withdrawing

34

inductive effect of -NO2

electron withdrawing

35

inductive effect of -CN

electron withdrawing

36

inductive effect of -CHO, -COR

electron withdrawing

37

inductive effect of -F, -Cl, -Br, -I, -CF3

electron withdrawing

38

inductive effect of -O-, -COO-

electron donating

39

inductive effect of -CH3, -CR3

electron donating

40

inductive effect of -CF3

electron withdrawing

41

resonance effects of -COOR, -COOH

electron withdrawing

42

resonance effects of -COR, -COH

electron withdrawing

43

resonance effects of -SO2R

electron withdrawing

44

resonance effects of -SO2NHR

electron withdrawing

45

resonance effects of -NO2

electron withdrawing

46

resonance effects of -CN

electron withdrawing

47

resonance effects of -Ar

electron withdrawing

48

resonance effects of -OH, -OR

electron donating

49

resonance effects of -NH2, -NR2

electron donating

50

resonance effects of -NHR2

electron donating

51

resonance effects of -SH

electron donating

52

delta G=

delta H - T delta S

53

H=

enthalpy (heat)

54

S=

entropy (disorder)

55

a compound that is predisposed to its active conformation has a _____ and should demonstrate _______

smaller entropy change/ an increased binding affinity

56

less rotation = ____ entropy

less

57

less rotation = _______ entropic penalty

less

58

________ prevents entropic penalty associated with adopting binding conformatiion

rigidification of carbon backbone

59

name three aromatic amino acids

tyr phe trp

60

goal of ring variation: maintain _____ and _________ interactions while improving _______ and _______

electronic/ pi stacking/ h-bonding/ pharmacokinetic

61

GI50 =

half growth inhibition concentration

62

Steps to generate IC50 values:

1.) test 8-10 concentrations of drug for biological activity. 2)measure biological activity and convert to a % value. Control = 100%, expreimental values are adjusted. 3) plot % of activity as a function of concentration

63

how many data points do you need to have on each side of a dose response curve?

at least 2-3

64

an IC50 change of >___ units is significant

10

65

list three H-bonding donors:

OH, NH2, NHR

66

list three h-bonding acceptors:

O, N, F