EXAM 3 - Structure-Activity Relationships (SAR) Flashcards
Why are structure-activity relationships the central tool of medicinal chemistry?
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.
Explain the significance of determining the binding site.
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.
What is it used for? How does X-ray crystallography work?
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
Describe structure-based design. What is it used for?
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.
Explain the potential problems of structure-based drug design.
- 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
Explain lead-based drug design (LBDD).
Designing a drug without knowing the binding site.
* there is no co-crystal structure
* step-wise changes that will lead to changes in potency
What are some potential problems of lead-based drug design?
- Increased number of compounds (bc we have to “guess”) to test for SAR purposess
- compounds designed “randomly”
Explain structure-activity relationships (SAR).
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?
Describe what a pharmacophore is.
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
Define auxophore.
The non-essential portion of a drug that supports the pharmacophore and can be modified to improve drug-like properties.
List the steps for SAR development.
- Identify regions of the lead compound to modify
- Synthesize new analogues with modifications to these regions –> do one modification at a time
- Evaluate activity of new analogues in our in vitro assay (multiple concentrations) to test activity
- Determine IC50 values for each analogue
- Compare IC50 analogue values
* determine how each structural modification affects biological activity against target.
C) Structure-based design allows for rational compound design based on clear snapshot of how the lead compound interacts with the binding pocket.
A) Lead-based drug design followed by structure-based drug design.
* goes from lead-based to co-crystal use
Explain what a bioisotere is.
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
What is the purpose of using bioisoteres?
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
List the three ways to optimize target interactions.
- functional group variation - modify easily accessible FGs
- functional group addition/subtraction
- spatial orientation - modify 3D location of functional groups rigidification and conformational blockers
Explain the purpose of optimizing target interactions within a compound.
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.
Describe what information can be collected from FG variation.
Simple variations can provide information about H-bonding, sterics, size, and electronic interactions.
Explain the information that can be gathered from FG addition/subtraction.
Addition of functional groups can identify new binding interactions and enhance electrostatic/hydrophobic/H-bond interactions.
What is an inductive effect?
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.
Explain what resonance effects are.
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
What effects can modifications of FGs on aromatics have?
- new/improved target interactions
- can alter acidity/basicity of other FGs on aromatic ring
- 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
Explain the Hammett substituent constant.
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
What is the significance of using deltaS in formation a compound.
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
Why is it beneficial to try to reduce inital entropy (S)?
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)
State the two purposes for rigidification of carbon backbones.
- Prevent flexibility to provide improved binding at active site.
- Prevent entropic penalty associated with adopting binding conformation
- Adopts shape of binding site
- increases selectivity
An IC50 change of ____ nm is considered significant.
greater than 10
Name the main H-bonding donors (3) and acceptors (2).
Donors: OH, NH2, NHR (contains H)
Acceptors: O (any), N (any)
Draw these groups: phenyl, cyclohexyl, alkene, alcohol, amine, and methoxy.
Search up on google for answer
List the general electron withdrawing groups.
COOR
COOH
NO2
CN
CF3
List the general electron donating groups.
NH2
OH
OR
CH3
Ph
Identify ortho, meta, and para positions.
