EXAM 3 - Structure-Activity Relationships (SAR)

Question 1

Why are structure-activity relationships the central tool of medicinal chemistry?

Answer 1

By modifying the structure of the lead compound/drug, it is going to modify the effect it has on target interactions.
* can change potency, selectivity, stability, etc.

Question 2

Explain the significance of determining the binding site.

Answer 2

Location on the target that is interacting with the lead compound
* allows visualization of the shape, size, and specific/potential intermolecular interactions between compound and target.
* You know what can fit into the binding site/pocket.

Question 3

What is it used for? How does X-ray crystallography work?

Answer 3

X-ray crystallography is used to determine the specific orientation of amino acids in a binding site (Intermolecular interactions between lead compound and protein target)
* proteins form crystals when they are purified and concentrated
* when a x-ray shines interacts with the crystal, a diffraction pattern is created (distinct pattern)
* pattern is analyzed to determine position of amino acids in the protein –> protein model

Question 4

Describe structure-based design. What is it used for?

Answer 4

3D structure of the co-crystal lead compound interacting with its binding site is known.
* allows you to design analogues that mimic the 3D structure that was determined using X-ray crystallography.
* if you are aware the binding site is long and narrow, you don’t want to make a circular drug bc it won’t fit.

Question 5

Explain the potential problems of structure-based drug design.

Answer 5

• not all proteins are responsive to x-ray crystallography
• ‘solving’ co-crystal structures is difficult (hard to determine co-crystal structure)
• co-crystal structure is a single, static snapshot of the protein –> protein binding is dynamic

Question 6

Explain lead-based drug design (LBDD).

Answer 6

Designing a drug without knowing the binding site.
* there is no co-crystal structure
* step-wise changes that will lead to changes in potency

Question 7

What are some potential problems of lead-based drug design?

Answer 7

• Increased number of compounds (bc we have to “guess”) to test for SAR purposess
• compounds designed “randomly”

Question 8

Explain structure-activity relationships (SAR).

Answer 8

Identify regions of the lead compound that are essential for biological activity and utilize this knowledge to enhance target interactions and improve activity
* how does changing one thing about the compound change the way it interacts with the target?

Question 9

Describe what a pharmacophore is.

Answer 9

Basic molecular structure of the lead compound that represents the functional groups required for biological activity and their spatial orientations relative to each other.
* if removing a hydroxyl group inactivates the compound
–> the hydroxyl group is part of the pharmacophore

Question 10

Define auxophore.

Answer 10

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

Question 11

List the steps for SAR development.

Answer 11

1. Identify regions of the lead compound to modify
2. Synthesize new analogues with modifications to these regions –> do one modification at a time
3. Evaluate activity of new analogues in our in vitro assay (multiple concentrations) to test activity
4. Determine IC50 values for each analogue
5. Compare IC50 analogue values
   * determine how each structural modification affects biological activity against target.

Question 12

Answer 12

C) Structure-based design allows for rational compound design based on clear snapshot of how the lead compound interacts with the binding pocket.

Question 13

Answer 13

A) Lead-based drug design followed by structure-based drug design.
* goes from lead-based to co-crystal use

Question 14

Explain what a bioisotere is.

Answer 14

Atoms or functional groups that share one or more of the following chemical and/or physical properties but also have one key difference.
* size, shape, H-bonding, electron-withdrawing/donating

Question 15

What is the purpose of using bioisoteres?

Answer 15

Used in SAR to identify effects of above characteristics at a single location of the lead compound.

ex. H and F
* equivalent in size
* very different electron-withdrawing
–> if they have different biological effects, you can conclude that it is bc of the electron-withdrawing properties

Question 16

List the three ways to optimize target interactions.

Answer 16

• functional group variation - modify easily accessible FGs
• functional group addition/subtraction
• spatial orientation - modify 3D location of functional groups rigidification and conformational blockers

Question 17

Explain the purpose of optimizing target interactions within a compound.

Answer 17

Enhance drug potency by improving intermolecular interactions between compound and binding site on target.
* hydrogen bonding, hydrophobic, electrostatic, steric (size), spatial orientation

Evaluate the greatest number of rationally-designed compounds in the least amount of time with the simplest chemistry.

Question 18

Describe what information can be collected from FG variation.

Answer 18

Simple variations can provide information about H-bonding, sterics, size, and electronic interactions.

Question 19

Explain the information that can be gathered from FG addition/subtraction.

Answer 19

Addition of functional groups can identify new binding interactions and enhance electrostatic/hydrophobic/H-bond interactions.

Question 20

What is an inductive effect?

Answer 20

Electronic effects of an atom or functional group that is contributed through a single bond.
* primarily a function of electronegativity

Image example: Cl is more electronegative so its going to pull the electron charge towards itself and away from OH. It makes Cl more basic and OH more acidic.

Question 21

Explain what resonance effects are.

Answer 21

Sharing of electrons between more than two atoms through delocalization of electrons across a pi-system.
* only for aromatic rings
* ex. electrons can be shared throughout whole orbital of benzene ring

Question 22

What effects can modifications of FGs on aromatics have?

Answer 22

1. new/improved target interactions
2. can alter acidity/basicity of other FGs on aromatic ring
3. decrease/increase electrostatic interactions with target based on electron donating/withdrawing nature of substituent
   * inductive effects will only impact the singular FG
   * resonance and inductive effects will affect the whole molecule and its binding

Question 23

Explain the Hammett substituent constant.

Answer 23

Measure of the electron donating/withdrawing ability of a substituent on an aromatic ring (also dependent on meta vs. para location)
* positive = electron-withdrawing, ex. Cl, CN, CF3
* negative = electron-donating, ex. Me, Et, t-Bu

Accounts for inductive and resonance effects

Question 24

What is the significance of using deltaS in formation a compound.

Answer 24

Large negative deltaS = non-spontaneous
Small negative deltaS = spontaneous

GOAL: SMALL NEGATIVE VALUE
Ex. If a compound has entropy of 100 to start. When it is bound, entropy is 10 –> deltaS = -90
* We can constrain the compound to its active conformation so it will bind better.
* Better alternative: Reduce to one active conformation where initial S = 30 and when it is bound, entropy = 10 –> deltaS = -20

Question 25

Why is it beneficial to try to reduce inital entropy (S)?

Answer 25

A compound that is predisposed to its active conformation has a smaller entropy change and an increased binding affinity.
* By reducing rotation of bonds –> less entropy –> less entropic penalty (more favorable)

Question 26

State the two purposes for rigidification of carbon backbones.

Answer 26

1. Prevent flexibility to provide improved binding at active site.
2. Prevent entropic penalty associated with adopting binding conformation

• Adopts shape of binding site
• increases selectivity

Question 27

An IC50 change of ____ nm is considered significant.

Answer 27

greater than 10

Question 28

Name the main H-bonding donors (3) and acceptors (2).

Answer 28

Donors: OH, NH2, NHR (contains H)

Acceptors: O (any), N (any)

Question 29

Draw these groups: phenyl, cyclohexyl, alkene, alcohol, amine, and methoxy.

Answer 29

Search up on google for answer

Question 30

List the general electron withdrawing groups.

Answer 30

COOR
COOH
NO2
CN
CF3

Question 31

List the general electron donating groups.

Answer 31

NH2
OH
OR
CH3
Ph

Question 32

Identify ortho, meta, and para positions.

Answer 32