Optimising Drug Structure Flashcards
What to identify when designing a new drug from a natural ligands or new lead compound
Types of interactions possible
Structural features that are important
Pharmocaphore
What is a pharmocaphore
Defines the atoms and functional groups required for a specific pharmacological activity, and their relative positions in space”
For a drug to fir into target protein site it must:
Fit into the site
Be held in place by complimentary binding interactions - more biding interactions the tighter it will bind
If it is greatly bound then less…
Less drug needed and less costs
Intermolecular binding interactions
Ionic
Hydrogen
Van der waals
Hydrophobic
Pi pi
Ionic bonds :
Strongest
Between opposite charges
Strength is inversely proportional to the distance between the 2 groups
Negatively charged FG’s
Can be deprotoated
- carboxylic acids
- sulfonic acids
- phosphates
Ositively charged FG’s:
Can be pronated
H3N-R
Any N containing mol with an avalible lone pair to pick up a proton
Hydrogen bods
Weaker than ionic but stronger than van der waals
Place betwen elector define int H and alavalible lone pai on heteroatom
HBA and HBD
HBD’s
Alcohol
Thrill
Amines
HBA’s
N O or S heteroatoms
Amine, alcohol, ester, thinly, ether, carboxylic, phosphates
Van der waals
Very weka
Between hydrophoic regions of drug and target
Drug mst be close to binding region for interaction to occur
Pi pi stacking
Non covalent interactions between aromatic rings containing pi bonds
Best overlap is when rings are on top of each other and a little of set
Very common
What are the binding roles of alcohols and phenols
Often used in H bonding
O is acceptor and H is donor
Bindin roles of aromatic rings
To test importance we replace it with a cyclohexane ring o is no longer flat and may not bind as well
Binding role of ketones and aldehydes
Carbonyl is planar and interacts as HBA
To test ipoartannce:
- reduce carbonyl to alcohol
- Changes the geometry to tetrahedral
- weakens H binding and dipole-dipole
Could also replace C=O with a CH2 group to see if HBD groups are important
Binding roles of amines
Protonated at physiological pH (7)
- it’s ionised and cannot act of HBA but can act as HBD and form strong H bonds
To test importance:
- convert to amide
- prevents N acting as HBA as the lone pair will interact with neighbouring carbonyl group
- also prevent protonated of N = no ionic interactions
Binding role of carboxylic
Can act as HBD and HBA
Binding role of esters
HBA only
What is a struture activity relationship SAR
Aims to discover which parts of the molecule are important for biological activity
Simple substitution
Varying substituents
Remove the group
Bioisosteres Structural simplific
Structural extension
Chain extension
Ring expansion/contraction Ring fusion
Ring variation
Alter 3D shape
Stereochemistry
Rigidification
Conformational blockers
Lipinskis rule
Molecular weight less than 500
No more than 5 HBD
No more than 10 HBA
LogP less than +5
How does hydrophobicity affect drug behaviour
How readily a drug crosses cell membranes
How a drug interacts with a protein receptor
Extension of the structure
- Lead compound wont necessarily hit all of the possible binding sites in a receptor
- Could add extra functional groups to the lead in order to probe for extra binding interactions * Often used to find extra hydrophobic regions
- Frequently used strategy to turn agonists into antagonists
Chain extension
Some drugs have two important binding groups linked together by a chain, in which case it is possible that the chain length is not ideal for the best interaction.
Therefore, shortening or lengthening the chain is a useful tactic to try.
Ring variations
- varying the rings in drug structures can lead to improved binding
- In particular, changing an aromatic ring to a heteroaromatic ring can often give new binding interactions
Bioisoster
Group that can be used to replace another group while retaining the desired biological activity
Often used to replace a FG that is important for target binding but it also problematic
Simplification of the structre
Removal of chiral carbons is a benefit ie statins
Rigidification
To lock a compound into active site
Can be used to increase activity
Can be ridgified by adding rigid FGs’ like double bonds, alkynes, amides or aromatic rings
