Structure Activity Relationships Flashcards
What are the five stages of hit to lead drug discovery?
screening of compound libraries, hits, optimized leads, IND candidates, candidate drugs
What kind of binding affinity would a “hit” have?
1-20 um
what kind of binding affinity would an optimized lead have?
0.1 -1 um
what kind of binding affinity would an IND candidate have?
0.01 um
In lead based drug design, the structure of the binding site _______ and compounds/ligands _____
is not known/ are known
lead - based drug design can lead to a model of the binding site via
Structure activity relationship studies
If you have no protein target crystal structure and no ligand or lead compound…
use high-throughput screeing to identify lead and crystalize protein
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
if you have a ligand or lead compound but no protein target crystal structure…
use lead based drug design - rational design of improved compounds
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
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
auxophore:
non-essential portion of a drug that supports the pharmacophore and can be modified to improve drug-like properties
the 2D pharmacophore - __________ are important
functional groups
3D pharmacophore - __________ is important
spatial orientation of groups
how do you evaluate the activity of new analogues during SAR development?
in vitro assays
to determine how strucutral modifications affect biological activity against target during SAR development…
determine IC50 or EC50 values for each analogue
IC50
half maximal inhibitory concentration
EC50
half maximal effective concentration
bioisoters for SAR:
atoms or functional groups that share one or more chemical/ physical characteristics and are very different in others
characteristics to compare between bioisoters for SAR
size, shape, h-bonding, electronic
bioisoters are used in SAR to
identify the effects of size, shape, h-bonding, electronic differences at a single location of the lead compound
H and F are bioisoters because they are the same in _____ and different in ____
size/ h-bonding and electronically
F and Cl are bioisoters because they are the same in ______ but different in __
h-bonding and electronically/ size
NH2 and CH3 are bioisoters because they are the same in ____ and different in ____
size/ hydrogen bonding
what are some ways to optimize spatial orientation when optimizing target interactions?
modify 3D location of functional groups, rigidification and conformational blockers
addition of functional groups can enhance __________ interactions
hydrophobic or ionic
inductive effects
refer to electronic effects of an atom or functional group that is contributed through a single bond
inductive effects are primarily a function of
electronegativity
resonance effects
sharing of electrons between more than two atoms through delocalization of electrons across a pi-system
Functional Group modifications on aromatics can alter _____ of _________
acidity or basicity/ other FGs on aromatic ring
resonance effects of FG modifications on aromatics:
structures are stabilized through resonance structures (pi system)
Inductive effect of -NR3+, -NH3+
electron withdrawing
inductive effect of -COOH, -COOR
electron withdrawing
inductive effect of -NO2
electron withdrawing
inductive effect of -CN
electron withdrawing
inductive effect of -CHO, -COR
electron withdrawing
inductive effect of -F, -Cl, -Br, -I, -CF3
electron withdrawing
inductive effect of -O-, -COO-
electron donating
inductive effect of -CH3, -CR3
electron donating
inductive effect of -CF3
electron withdrawing
resonance effects of -COOR, -COOH
electron withdrawing
resonance effects of -COR, -COH
electron withdrawing
resonance effects of -SO2R
electron withdrawing
resonance effects of -SO2NHR
electron withdrawing
resonance effects of -NO2
electron withdrawing
resonance effects of -CN
electron withdrawing
resonance effects of -Ar
electron withdrawing
resonance effects of -OH, -OR
electron donating
resonance effects of -NH2, -NR2
electron donating
resonance effects of -NHR2
electron donating
resonance effects of -SH
electron donating
delta G=
delta H - T delta S
H=
enthalpy (heat)
S=
entropy (disorder)
a compound that is predisposed to its active conformation has a _____ and should demonstrate _______
smaller entropy change/ an increased binding affinity
less rotation = ____ entropy
less
less rotation = _______ entropic penalty
less
________ prevents entropic penalty associated with adopting binding conformatiion
rigidification of carbon backbone
name three aromatic amino acids
tyr phe trp
goal of ring variation: maintain _____ and _________ interactions while improving _______ and _______
electronic/ pi stacking/ h-bonding/ pharmacokinetic
GI50 =
half growth inhibition concentration
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
how many data points do you need to have on each side of a dose response curve?
at least 2-3
an IC50 change of >___ units is significant
10
list three H-bonding donors:
OH, NH2, NHR
list three h-bonding acceptors:
O, N, F
